_:b560322148 . _:b560322233 . _:b560322451 . _:b560322232 . . _:b560322276 . _:b560322235 . _:b560322383 . _:b560322418 . _:b560322135 . _:b560322091 . . _:b560322234 . _:b560322168 . _:b560322169 . _:b560322245 . _:b560322170 . _:b560322459 . _:b560322171 . _:b560322172 . _:b560322173 . _:b560322244 . _:b560322174 . _:b560322166 . _:b560322175 . _:b560322160 . _:b560322161 . _:b560322247 . _:b560322105 . . _:b560322162 . _:b560322163 . _:b560322164 . _:b560322275 . _:b560322165 . _:b560322246 . _:b560322166 . _:b560322465 . _:b560322167 . . _:b560322152 . . _:b560322153 . _:b560322241 . _:b560322154 . . _:b560322155 . _:b560322156 . _:b560322157 . _:b560322240 . _:b560322158 . _:b560322159 . _:b560322522 . _:b560322144 . . _:b560322144 . _:b560322145 . _:b560322351 . _:b560322243 . . _:b560322146 . _:b560322147 . _:b560322469 . _:b560322212 . _:b560322147 . _:b560322148 . _:b560322149 . _:b560322242 . . _:b560322150 . _:b560322151 . _:b560322136 . _:b560322137 . _:b560322253 . _:b560322138 . _:b560322530 . . _:b560322139 . _:b560322140 . _:b560322146 . _:b560322141 . _:b560322252 . _:b560322142 . _:b560322143 . _:b560322128 . _:b33942564 "The isogenic pairs of EGFR TKI sensitive and EGFR TKI resistant cell lines used in these studies, including PC-9/PC-9 ERc1, HCC4006/HCC4006 ER, HCC827/HCC827 ER, and HCC2279/HCC2279 ER, have been previously described21,>>22<<. The EGFR TKI resistant cells (denoted \u2018ER\u2019 for Erlotinib Resistant) were continuously grown in 1 \u03BCM erlotinib. All cell lines were maintained in RPMI 1640 medium (Mediatech, Inc., Manassas, VA, USA) supplemented with 10% heat inactivated" . _:b560322092 . _:b560322129 . _:b560322255 . _:b560322130 . _:b560322131 . _:b560322132 . . _:b560322133 . _:b560322512 . _:b560322331 . _:b560322254 . _:b560322134 . _:b560322135 . _:b560322120 . _:b560322121 . _:b560322249 . _:b560322122 . . _:b560322123 . _:b560322124 . _:b560322125 . _:b560322248 . _:b560322126 . _:b560322114 . . _:b560322127 . _:b560322112 . _:b560322113 . _:b560322251 . _:b560322114 . _:b560322115 . _:b560322116 . _:b560322545 . _:b560322117 . _:b560322250 . _:b560322118 . _:b560322119 . . _:b33942538 "introduction" . _:b560322104 . _:b560322105 . _:b560322261 . _:b560322106 . _:b560322107 . _:b560322108 . _:b560322304 . _:b560322109 . _:b560322533 . _:b560322260 . _:b560322110 . _:b560322111 . _:b560322493 . _:b560322096 . _:b560322097 . _:b560322263 . _:b560322098 . _:b560322099 . . _:b560322100 . _:b560322101 . _:b560322262 . _:b560322102 . _:b560322103 . _:b560322088 . _:b560322490 . _:b560322089 . _:b560322257 . _:b560322090 . _:b560322091 . _:b560322092 . . _:b560322093 . _:b560322256 . _:b560322094 . _:b560322219 . _:b560322095 . _:b560322080 . _:b560322081 . _:b560322259 . . _:b560322082 . _:b560322083 . _:b560322084 . _:b560322085 . _:b560322258 . _:b560322086 . _:b560322087 . _:b560322534 . _:b560322269 . _:b560322074 . _:b560322075 . _:b560322074 "32"^^ . _:b560322157 . _:b560322076 . _:b560322077 . _:b560322268 . _:b560322078 . _:b560322417 . _:b560322079 . _:b560322271 . _:b560322218 . _:b560322270 . . _:b560322145 . _:b560322265 . . _:b560322515 . _:b560322264 . _:b560322267 . _:b560322362 . . . _:b560322177 . . _:b33942549 "4a,b), as previously described>>15<<. These cells did not have any \u2018second-site\u2019 ALK kinase domain mutations (data not shown)." . _:b560322266 . . _:b560322296 . _:b560322297 . _:b560322277 . _:b560322298 . _:b560322299 . _:b560322300 . _:b560322257 . _:b560322301 . _:b560322276 . _:b560322302 . _:b560322303 . _:b560322288 . _:b33942569 "Drug synergism was assessed using the Mix-Low method>>9<<. For soft agar assays, cells were seeded in 96 well plates and treated with drug according to the manufacturer's instructions (Cell Biolabs, Inc., San Diego, CA, USA)." . _:b560322289 . _:b560322279 . _:b560322290 . _:b560322291 . _:b560322292 . _:b560322293 . _:b560322278 . . _:b560322294 . _:b560322295 . _:b560322280 . _:b560322281 . _:b33942570 . _:b560322273 . _:b560322282 . _:b560322283 . _:b560322401 . _:b560322284 . _:b560322285 . _:b560322468 . _:b560322272 . _:b560322286 . . _:b560322287 . _:b33942546 . _:b560322272 . _:b560322273 . _:b560322275 . _:b560322274 . . _:b560322275 . _:b560322276 . _:b560322277 . _:b560322274 . _:b560322278 . _:b560322335 . _:b560322279 . _:b560322422 . _:b560322264 . _:b560322531 . _:b560322265 . _:b560322285 . _:b560322266 . _:b560322267 . _:b560322443 . _:b560322268 . _:b560322269 . _:b560322284 . _:b560322270 . _:b560322199 . _:b560322271 . _:b560322256 . _:b560322257 . _:b560322287 . . _:b560322258 . _:b560322259 . _:b560322075 "28"^^ . _:b560322260 . . _:b560322261 . _:b560322286 . _:b560322262 . _:b560322263 . _:b560322248 . _:b560322510 . _:b560322249 . _:b560322281 . _:b560322250 . _:b560322251 . _:b560322252 . _:b560322409 . _:b560322253 . _:b560322280 . _:b560322241 . _:b560322254 . _:b560322255 . _:b560322240 . _:b560322241 . _:b560322338 . _:b560322283 . _:b560322151 . _:b560322078 "22"^^ . _:b560322242 . _:b560322243 . _:b560322244 . _:b560322245 . _:b560322282 . _:b560322246 . _:b560322247 . _:b560322232 . _:b560322437 . _:b560322233 . _:b560322293 . _:b560322234 . _:b560322076 "23"^^ . _:b560322235 . _:b560322236 . _:b33942557 "The second-generation ALK TKI, LDK-378 (ceritinib), has demonstrated a 56% ORR in patients with ALK+ lung cancer who have progressed on crizotinib>>24<<. Yet, only a minority of patients had ALK alterations, suggesting the possibility of alternative \u2018bypass\u2019 mechanisms which are sensitive to LDK-378." . _:b560322079 "21"^^ . _:b560322237 . _:b560322292 . . _:b560322077 "22"^^ . . _:b560322584 . _:b560322238 . _:b560322585 . _:b560322239 . . _:b560322224 . _:b560322225 . _:b560322295 . _:b560322226 . _:b560322081 "19"^^ . _:b560322227 . _:b560322228 . _:b560322229 . _:b560322294 . . _:b560322576 . _:b560322230 . _:b560322577 . _:b560322231 . . . _:b560322080 "20"^^ . _:b560322578 . _:b560322216 . _:b560322579 . _:b560322217 . _:b560322289 . . _:b560322580 . _:b560322218 . _:b560322581 . _:b560322219 . . _:b560322582 . _:b560322220 . . _:b560322583 . _:b560322221 . _:b560322288 . . _:b560322568 . _:b560322222 . _:b560322082 "19"^^ . . _:b560322569 . _:b560322223 . _:b560322570 . _:b560322208 . . _:b560322083 "17"^^ . _:b560322571 . _:b560322209 . _:b560322291 . _:b560322572 . _:b560322210 . _:b560322573 . _:b560322211 . _:b560322574 . _:b560322212 . _:b560322084 "17"^^ . _:b560322575 . _:b560322213 . _:b560322290 . _:b560322560 . _:b560322214 . _:b560322370 . _:b560322561 . _:b560322215 . _:b560322085 "16"^^ . _:b560322562 . _:b560322200 . _:b560322563 . _:b560322201 . _:b560322301 . _:b560322564 . _:b560322202 . _:b560322086 "15"^^ . _:b560322565 . _:b560322203 . _:b560322566 . _:b560322204 . _:b560322567 . _:b560322205 . _:b560322300 . _:b560322206 . _:b560322087 "15"^^ . _:b560322207 . . _:b560322192 . _:b560322193 . _:b560322303 . _:b560322088 "14"^^ . _:b560322194 . _:b560322195 . _:b560322095 "12"^^ . _:b560322196 . _:b560322256 . _:b560322197 . _:b560322302 . _:b560322272 . _:b560322089 "14"^^ . _:b560322198 . _:b560322199 . _:b560322094 "12"^^ . _:b560322184 . _:b560322185 . _:b560322297 . _:b560322090 "14"^^ . _:b560322186 . . _:b560322187 . _:b560322193 . _:b560322176 . _:b560322093 "12"^^ . _:b560322188 . _:b560322288 . _:b560322189 . _:b560322296 . _:b560322190 . _:b560322191 . . _:b560322092 "12"^^ . _:b560322176 . _:b560322177 . _:b560322299 . _:b560322178 . _:b560322179 . _:b560322180 . _:b560322255 . _:b560322235 . _:b560322091 "13"^^ . _:b560322181 . _:b560322396 . _:b560322298 . _:b560322182 . _:b560322567 . . _:b560322183 . . _:b560322424 . _:b560322402 . . _:b560322425 . _:b560322088 . . _:b560322426 . _:b560322427 . . _:b560322428 . _:b560322429 . _:b560322537 . _:b560322430 . _:b560322431 . _:b560322202 . _:b560322416 . _:b560322417 . _:b560322103 "10"^^ . _:b560322418 . . . _:b33942554 . _:b560322419 . _:b560322420 . _:b560322375 . _:b560322421 . _:b560322102 "10"^^ . _:b560322422 . _:b560322423 . _:b560322408 . _:b560322409 . _:b560322101 "10"^^ . . _:b560322410 . _:b560322411 . . _:b560322412 . _:b560322413 . _:b560322100 "10"^^ . _:b560322414 . _:b560322415 . . . _:b560322400 . _:b560322401 . _:b560322099 "10"^^ . _:b560322402 . _:b560322403 . _:b560322404 . _:b560322405 . _:b560322406 . _:b560322098 "11"^^ . _:b560322407 . . _:b560322392 . _:b560322393 . _:b560322455 . _:b560322394 . _:b560322097 "11"^^ . _:b560322395 . _:b560322396 . _:b560322397 . _:b560322246 . _:b560322075 . _:b560322398 . _:b560322096 "11"^^ . . _:b560322399 . _:b560322384 . _:b560322385 . _:b560322386 . _:b560322387 . _:b560322388 . _:b560322110 "9"^^ . . _:b560322389 . _:b560322390 . . _:b560322391 . _:b560322111 "8"^^ . . _:b560322376 . _:b560322081 . _:b560322377 . _:b560322544 . _:b560322378 . . _:b560322379 . . _:b560322380 . _:b560322108 "9"^^ . _:b560322381 . . _:b560322382 . _:b560322383 . _:b560322368 . _:b560322109 "9"^^ . . _:b560322369 . . . _:b560322097 . _:b560322370 . _:b560322371 . _:b560322372 . _:b560322106 "9"^^ . _:b560322373 . _:b560322374 . _:b560322291 . _:b560322375 . _:b560322360 . _:b560322107 "9"^^ . . _:b560322361 . _:b560322355 . _:b560322362 . _:b560322363 . _:b560322364 . _:b33942543 . _:b560322365 . _:b560322190 . _:b560322104 "10"^^ . _:b560322366 . _:b560322471 . _:b560322367 . _:b560322352 . _:b560322105 "9"^^ . _:b560322353 . _:b560322354 . _:b560322355 . _:b560322205 . _:b560322118 "8"^^ . _:b560322356 . _:b560322131 . _:b560322357 . _:b560322358 . _:b560322359 . _:b560322119 "8"^^ . _:b560322344 . _:b560322372 . _:b560322345 . _:b560322346 . _:b560322347 . _:b560322430 . _:b560322116 "8"^^ . _:b560322348 . _:b560322349 . _:b560322350 . _:b560322539 . _:b560322351 . _:b560322117 "8"^^ . _:b560322336 . _:b560322337 . _:b560322338 . _:b560322390 . _:b560322339 . _:b560322114 "8"^^ . _:b560322340 . . _:b560322341 . _:b560322342 . _:b560322343 . _:b560322115 "8"^^ . . . _:b560322328 . _:b560322329 . . _:b560322330 . _:b560322331 . _:b560322416 . _:b560322112 "8"^^ . _:b560322332 . _:b560322247 . _:b560322333 . _:b560322334 . _:b560322335 . _:b560322113 "8"^^ . _:b560322320 . _:b560322282 . _:b560322321 . . _:b560322126 "7"^^ . _:b560322322 . _:b560322323 . _:b560322278 . _:b560322324 . _:b560322325 . _:b560322326 . _:b560322127 "7"^^ . _:b560322327 . _:b560322312 . _:b560322313 . _:b560322314 . _:b560322124 "7"^^ . _:b560322315 . _:b560322316 . _:b560322317 . . _:b560322318 . _:b560322125 "7"^^ . . _:b560322286 . _:b560322319 . _:b560322304 . _:b33942540 . _:b560322305 . _:b560322306 . _:b560322307 . _:b560322122 "8"^^ . _:b560322308 . _:b33942541 . _:b560322309 . _:b560322310 . _:b560322290 . _:b560322123 "7"^^ . _:b560322311 . _:b560322365 . _:b560322552 . _:b33942542 . _:b560322525 . _:b560322553 . _:b560322554 . _:b560322555 . _:b560322120 "8"^^ . _:b560322556 . _:b33942543 . _:b560322577 . _:b560322557 . _:b560322558 . _:b560322559 . _:b560322121 "8"^^ . _:b560322544 . _:b560322545 . _:b560322134 "6"^^ . _:b560322546 . _:b560322547 . _:b560322548 . . _:b560322135 "6"^^ . _:b560322549 . . _:b560322550 . . . _:b560322551 . _:b560322536 . _:b33942538 . _:b560322537 . . _:b560322132 "7"^^ . _:b560322538 . _:b560322539 . _:b560322540 . _:b33942539 . _:b560322541 . _:b560322133 "6"^^ . . _:b560322542 . _:b560322543 . _:b560322528 . _:b33942548 . _:b560322529 . _:b560322530 . _:b560322130 "7"^^ . _:b560322531 . _:b560322532 . _:b33942549 . _:b560322533 . . _:b560322131 "7"^^ . _:b560322087 . _:b560322534 . _:b560322535 . _:b560322520 . _:b33942550 . _:b560322521 . _:b33942550 "IGFBP3 is known to block IGF-1 induced activation of IGF-1R>>16<<,17. Overall, these studies show that the IGF-1R signaling pathway is activated by multiple mechanisms in H3122 XR cells." . _:b560322364 . _:b560322349 . _:b560322085 . . _:b560322522 . _:b560322128 "7"^^ . . _:b560322523 . _:b560322524 . _:b33942551 . . _:b560322525 . _:b560322526 . _:b560322129 "7"^^ . _:b560322527 . . _:b560322512 . _:b33942544 . _:b560322513 . _:b560322366 . _:b560322142 "6"^^ . _:b560322514 . _:b560322515 . _:b560322516 . _:b33942545 . . _:b560322517 . _:b560322502 . _:b560322143 "6"^^ . . _:b560322518 . _:b560322519 . . _:b560322504 . _:b33942546 . _:b560322505 . _:b560322140 "6"^^ . _:b560322506 . _:b560322507 . _:b560322508 . _:b33942547 . _:b560322509 . _:b560322141 "6"^^ . _:b560322510 . _:b560322511 . _:b560322496 . _:b33942556 . _:b560322497 . _:b560322138 "6"^^ . _:b33942559 "discussion" . . . _:b560322498 . _:b560322499 . _:b560322500 . _:b33942557 . _:b560322497 . _:b560322501 . _:b560322139 "6"^^ . _:b560322502 . _:b560322503 . _:b560322488 . _:b33942558 . _:b560322489 . _:b560322313 . _:b560322136 "6"^^ . _:b560322490 . _:b560322423 . _:b560322491 . _:b560322492 . _:b33942573 "For the index patient's tumor, clinical genotyping was performed using the SNaPshot platform as previously described>>32<<." . _:b560322082 . _:b560322137 "6"^^ . _:b560322493 . _:b33942559 . . _:b560322494 . _:b33942571 "For analysis, the sample probe profile data in the GeneSpring export format was transformed to log-2 scale and normalized using quantile method by applying beadarray package>>31<< in BioConductor 2.11." . . _:b560322495 . _:b560322480 . _:b33942552 . _:b560322481 . _:b560322150 "6"^^ . _:b560322482 . . _:b560322483 . _:b560322484 . _:b33942553 . _:b560322485 . _:b560322486 . _:b560322487 . _:b560322472 . _:b33942554 . _:b560322473 . _:b560322148 "6"^^ . . . _:b560322309 . _:b560322474 . _:b560322475 . _:b560322476 . _:b33942555 . _:b560322151 "5"^^ . . _:b560322477 . _:b560322149 "6"^^ . _:b560322478 . _:b560322216 . . _:b560322479 . _:b560322464 . _:b33942564 . _:b560322465 . _:b560322146 "6"^^ . _:b560322466 . _:b560322467 . _:b560322223 . _:b560322468 . _:b33942569 . _:b33942565 . _:b560322469 . _:b560322147 "6"^^ . _:b560322470 . _:b560322471 . _:b560322456 . _:b33942566 . . _:b560322296 . _:b560322144 "6"^^ . _:b560322457 . _:b560322458 . _:b560322459 . _:b560322163 . _:b560322460 . _:b33942567 . _:b560322461 . _:b560322145 "6"^^ . _:b560322462 . _:b560322516 . _:b560322463 . _:b560322448 . _:b33942560 . _:b560322111 . _:b560322242 . _:b560322449 . _:b560322175 . _:b560322153 . _:b560322450 . _:b560322451 . _:b560322452 . _:b560322157 "5"^^ . . _:b560322453 . _:b33942561 . _:b560322454 . _:b560322463 . _:b560322376 . "PMC0" . _:b560322455 . _:b560322440 . _:b33942562 . _:b560322384 . _:b560322156 "5"^^ . _:b560322441 . _:b560322442 . . _:b560322443 . _:b560322444 . _:b33942563 . _:b560322252 . _:b560322159 "5"^^ . . _:b560322445 . _:b560322446 . . _:b560322447 . _:b560322432 . _:b33942572 . _:b560322158 "5"^^ . _:b560322433 . _:b560322434 . _:b560322435 . _:b560322436 . _:b33942573 . _:b560322153 "5"^^ . _:b560322437 . _:b560322438 . _:b560322439 . _:b560322152 "5"^^ . _:b560322538 . _:b560322501 . _:b560322581 . . _:b560322155 "5"^^ . . . . _:b33942568 . _:b560322154 "5"^^ . _:b560322165 "5"^^ . _:b33942569 . _:b33942545 "IRS-1 is a well-known substrate and adaptor protein for IGF-1R>>11<<, and IRS-1 has been demonstrated to be a primary adaptor for PI3K activation in H3122 cells12." . . . _:b560322265 . . _:b560322164 "5"^^ . _:b33942570 . _:b560322572 . . . . _:b33942572 "Genetically engineered mice harboring the EML4-ALK E13;A20 fusion variant has been previously reported>>13<<. Three month old mice from both genders were used in the described studies. All animal treatment studies were reviewed and approved by the IACUC at the Dana-Farber Cancer Institute." . . _:b33942571 . _:b33942548 "4b), a more potent and more specific ALK inhibitor>>14<<. Notably, a derivative of X-376 (X-396) is currently in phase I clinical trials (NCT01625234)." . _:b560322167 "5"^^ . . _:b560322166 "5"^^ . _:b560322485 . _:b560322582 . _:b560322133 . _:b560322161 "5"^^ . . _:b560322486 . _:b560322345 . _:b560322160 "5"^^ . . _:b560322517 . _:b560322358 . _:b560322163 "5"^^ . . _:b560322104 . _:b560322162 "5"^^ . _:b560322169 . _:b560322109 . _:b560322173 "5"^^ . . _:b560322172 "5"^^ . _:b560322175 "5"^^ . _:b560322174 "5"^^ . _:b560322393 . . _:b560322169 "5"^^ . _:b560322168 "5"^^ . . . _:b560322171 "5"^^ . . _:b560322170 "5"^^ . . _:b560322181 "4"^^ . _:b560322558 . . . . _:b560322180 "4"^^ . _:b560322267 . _:b560322183 "4"^^ . _:b560322498 . . _:b560322182 "4"^^ . _:b560322154 . _:b560322177 "5"^^ . . . _:b560322229 . . _:b560322176 "5"^^ . _:b560322179 "5"^^ . _:b560322477 . . . _:b560322178 "5"^^ . _:b560322189 "4"^^ . _:b560322103 . _:b560322559 . . . _:b560322188 "4"^^ . _:b560322101 . . . . _:b560322388 . . . _:b560322191 "4"^^ . _:b560322528 . _:b560322483 . _:b560322190 "4"^^ . . _:b560322185 "4"^^ . . _:b560322184 "4"^^ . _:b560322472 . . _:b560322500 . _:b33942556 "As an orthogonal approach, we performed mRNA expression analysis for IGF-1R and IRS-1 using Nanostring>>23<< on matched patient samples and on isogenic pairs of ALK TKI-sensitive and resistant cell lines." . _:b560322187 "4"^^ . . . _:b560322186 "4"^^ . . _:b560322197 "4"^^ . . . _:b560322196 "4"^^ . _:b560322244 . _:b560322367 . . . _:b560322199 "4"^^ . . . _:b560322198 "4"^^ . _:b560322532 . _:b560322193 "4"^^ . _:b560322281 . . _:b560322309 . . _:b33942541 "results" . . _:b560322192 "4"^^ . _:b560322308 . _:b560322556 . _:b560322195 "4"^^ . _:b560322311 . _:b560322194 "4"^^ . _:b560322310 . . _:b560322192 . _:b560322205 "4"^^ . _:b560322305 . _:b560322551 . _:b560322204 "4"^^ . . _:b560322304 . . _:b560322207 "4"^^ . _:b560322307 . . _:b560322206 "4"^^ . . _:b560322306 . . _:b560322201 "4"^^ . _:b560322317 . _:b560322200 "4"^^ . _:b33942550 . _:b560322316 . _:b560322363 . _:b560322203 "4"^^ . _:b560322319 . . _:b560322202 "4"^^ . _:b560322318 . _:b560322447 . . . _:b560322341 . _:b560322213 "4"^^ . _:b560322313 . _:b560322212 "4"^^ . _:b560322312 . _:b560322333 . . _:b560322215 "4"^^ . _:b560322315 . _:b560322214 "4"^^ . _:b560322314 . _:b560322380 . _:b560322209 "4"^^ . _:b560322520 . . _:b560322325 . _:b560322208 "4"^^ . _:b560322324 . . . . _:b560322211 "4"^^ . _:b560322327 . _:b560322210 "4"^^ . . _:b560322326 . . _:b560322221 "4"^^ . _:b560322095 . _:b560322321 . . _:b560322489 . _:b560322220 "4"^^ . _:b560322356 . . _:b560322320 . _:b560322223 "4"^^ . _:b560322323 . . _:b560322529 . _:b560322222 "4"^^ . _:b560322322 . . _:b560322217 "4"^^ . _:b560322333 . _:b560322086 . . _:b560322492 . _:b560322340 . _:b560322216 "4"^^ . _:b560322332 . . _:b560322219 "4"^^ . _:b560322335 . _:b560322579 . . . _:b560322218 "4"^^ . . _:b560322334 . _:b560322229 "3"^^ . _:b560322476 . _:b560322329 . . _:b560322482 . _:b560322285 . _:b560322228 "4"^^ . _:b560322240 . _:b560322328 . _:b560322231 "3"^^ . _:b560322555 . . _:b560322564 . _:b560322331 . _:b560322230 "3"^^ . _:b560322330 . . . _:b560322225 "4"^^ . _:b560322112 . _:b560322575 . _:b560322341 . _:b560322404 . . _:b560322344 . _:b560322224 "4"^^ . _:b560322340 . . _:b560322227 "4"^^ . . _:b560322343 . _:b560322236 . _:b560322429 . _:b560322226 "4"^^ . _:b560322543 . _:b560322342 . _:b560322237 "3"^^ . _:b560322357 . _:b560322337 . . _:b560322236 "3"^^ . _:b560322336 . _:b560322239 "3"^^ . _:b560322289 . _:b560322339 . . _:b560322238 "3"^^ . _:b33942539 "Genomic alterations in the anaplastic lymphoma kinase (ALK) gene are found in numerous malignancies>>1<<. In a phase I trial, the ALK tyrosine kinase inhibitor (TKI), crizotinib, induced an objective radiographic response (ORR) of 60.8% and a median progression-free survival of 9.7 months2." . _:b560322338 . . _:b560322233 "3"^^ . . _:b560322349 . _:b560322168 . _:b560322277 . _:b560322232 "3"^^ . _:b560322237 . . _:b560322348 . . _:b560322235 "3"^^ . _:b560322351 . _:b33942546 "IRS-1 is a well-known substrate and adaptor protein for IGF-1R11, and IRS-1 has been demonstrated to be a primary adaptor for PI3K activation in H3122 cells>>12<<. However, the precise mechanism whereby ALK fusion proteins link to effector pathways remains undefined. We observed that IRS-1 levels decreased with crizotinib treatment (Fig. 3b). Using lysates from H3122 cells, we found that ALK and" . . _:b560322234 "3"^^ . _:b560322126 . _:b560322162 . . _:b560322350 . _:b560322245 "3"^^ . _:b560322345 . _:b33942568 . . _:b560322244 "3"^^ . _:b560322344 . _:b560322247 "3"^^ . _:b560322450 . _:b560322549 . _:b560322347 . _:b560322246 "3"^^ . _:b560322346 . _:b560322241 "3"^^ . . _:b560322287 . _:b560322357 . _:b560322240 "3"^^ . . _:b560322356 . . _:b560322243 "3"^^ . _:b560322359 . _:b560322242 "3"^^ . . _:b560322449 . _:b560322358 . _:b560322253 "3"^^ . _:b560322353 . _:b560322137 . _:b560322252 "3"^^ . _:b560322452 . . _:b560322352 . _:b560322255 "3"^^ . . _:b560322355 . _:b33942562 . . _:b560322254 "3"^^ . . _:b560322354 . _:b560322167 . _:b560322249 "3"^^ . . _:b560322314 . _:b560322389 . _:b560322365 . _:b560322248 "3"^^ . _:b560322364 . _:b560322251 "3"^^ . . _:b560322367 . _:b560322406 . . _:b560322250 "3"^^ . _:b560322366 . _:b560322261 "3"^^ . _:b33942568 "X-376 was prepared as described previously>>14<<. Crizotinib (ChemieTek, Indianapolis, IN, USA), OSI-906 (Selleck Chemicals, Houston, TX, USA), AEW-541 (Selleck Chemicals, Houston, TX, USA), LDK-378 (Selleck Chemicals, Houston, TX, USA) and Lapatinib (Selleck Chemicals, Houston, TX," . _:b560322115 . . _:b560322496 . _:b560322361 . _:b560322260 "3"^^ . _:b560322360 . _:b560322425 . . _:b560322263 "3"^^ . . _:b560322306 . _:b560322318 . _:b560322363 . . _:b560322262 "3"^^ . . _:b560322362 . . _:b560322466 . _:b560322257 "3"^^ . _:b560322373 . . _:b560322256 "3"^^ . _:b560322280 . . _:b560322372 . _:b560322084 . _:b560322259 "3"^^ . . _:b560322375 . _:b560322258 "3"^^ . . . _:b560322374 . _:b33942544 . _:b560322269 "3"^^ . _:b560322369 . _:b560322268 "3"^^ . _:b560322368 . _:b560322200 . _:b560322271 "3"^^ . _:b560322371 . _:b560322270 "3"^^ . _:b33942553 . . _:b560322370 . _:b560322518 . . _:b560322317 . _:b560322265 "3"^^ . . _:b560322381 . _:b560322513 . _:b560322264 "3"^^ . _:b560322380 . _:b560322267 "3"^^ . _:b560322260 . _:b560322383 . _:b560322266 "3"^^ . _:b560322120 . _:b33942545 . . _:b560322382 . _:b560322277 "3"^^ . _:b560322326 . _:b560322377 . _:b560322276 "3"^^ . _:b560322303 . _:b560322376 . _:b560322279 "3"^^ . . _:b560322379 . _:b560322278 "3"^^ . _:b560322378 . _:b560322273 "3"^^ . _:b560322292 . _:b560322389 . _:b560322150 . _:b560322553 . _:b560322272 "3"^^ . _:b560322388 . _:b560322096 . _:b560322275 "3"^^ . _:b560322361 . . _:b560322238 . _:b560322391 . _:b560322274 "3"^^ . _:b560322557 . _:b560322390 . _:b33942567 "To obtain the best call set possible, we also used the software GATK>>29<< to do realignment and recalibration." . _:b560322285 "3"^^ . . _:b560322385 . . _:b560322118 . . _:b560322284 "3"^^ . . _:b560322420 . _:b560322384 . . _:b560322287 "3"^^ . _:b560322398 . . . _:b560322387 . . _:b560322286 "3"^^ . . _:b560322386 . _:b560322281 "3"^^ . _:b560322397 . . _:b560322280 "3"^^ . _:b560322396 . . _:b560322283 "3"^^ . _:b560322399 . _:b560322282 "3"^^ . _:b560322566 . . _:b560322398 . _:b560322295 . . _:b560322079 . _:b560322293 "3"^^ . _:b560322393 . _:b33942573 . . _:b560322292 "3"^^ . . _:b560322392 . _:b560322295 "3"^^ . . _:b560322395 . _:b560322294 "3"^^ . _:b560322394 . _:b560322161 . _:b560322289 "3"^^ . _:b560322405 . _:b33942548 . _:b560322428 . _:b560322288 "3"^^ . . _:b560322404 . _:b560322291 "3"^^ . _:b560322196 . _:b560322561 . _:b560322407 . _:b560322290 "3"^^ . . _:b560322406 . _:b560322130 . _:b560322301 "3"^^ . _:b560322401 . _:b560322122 . . _:b560322321 . _:b560322300 "3"^^ . _:b560322187 . _:b560322448 . _:b560322438 . . _:b560322400 . _:b560322303 "3"^^ . _:b560322182 . _:b560322475 . _:b560322403 . . _:b560322302 "3"^^ . . . _:b560322402 . . _:b560322297 "3"^^ . . _:b560322413 . _:b33942563 "The human anaplastic lymphoma cell line, SUDHL-1, has been previously described>>26<<. The isogenic pairs of EGFR TKI sensitive and EGFR TKI resistant cell lines used in these studies, including PC-9/PC-9 ERc1, HCC4006/HCC4006 ER, HCC827/HCC827 ER, and HCC2279/HCC2279 ER, have been previously described21,22. The EGFR TKI" . _:b560322296 "3"^^ . _:b560322254 . _:b560322412 . _:b560322299 "3"^^ . _:b560322094 . _:b560322089 . _:b560322415 . . _:b560322298 "3"^^ . _:b560322414 . _:b560322309 "3"^^ . _:b560322409 . . _:b560322308 "3"^^ . _:b560322385 . . _:b560322408 . . _:b560322311 "3"^^ . _:b560322411 . . _:b560322315 . _:b560322310 "3"^^ . _:b560322410 . _:b560322305 "3"^^ . _:b33942566 . _:b560322421 . _:b560322304 "3"^^ . _:b560322420 . _:b560322204 . _:b560322307 "3"^^ . _:b560322423 . . _:b560322306 "3"^^ . . _:b560322422 . _:b560322134 . _:b560322317 "3"^^ . _:b560322417 . . _:b560322316 "3"^^ . . . _:b560322416 . . _:b560322319 "3"^^ . . _:b560322392 . _:b560322419 . _:b560322318 "3"^^ . . _:b560322418 . . _:b560322298 . . . _:b560322313 "3"^^ . _:b560322429 . _:b560322312 "3"^^ . _:b33942558 . _:b560322428 . _:b560322315 "3"^^ . _:b560322431 . _:b560322314 "3"^^ . . . _:b560322430 . _:b560322325 "2"^^ . _:b560322474 . _:b560322425 . . _:b560322324 "2"^^ . _:b560322189 . _:b560322397 . . _:b560322424 . _:b560322327 "2"^^ . _:b560322263 . _:b560322427 . _:b560322316 . _:b560322326 "2"^^ . . _:b560322183 . . _:b560322156 . _:b560322426 . _:b560322321 "2"^^ . . _:b560322301 . . _:b560322437 . . _:b560322320 "3"^^ . _:b560322436 . _:b560322323 "2"^^ . . . . _:b560322439 . . _:b560322322 "2"^^ . . _:b560322098 . . _:b560322438 . _:b560322333 "2"^^ . _:b560322343 . _:b560322433 . _:b560322332 "2"^^ . _:b560322346 . _:b560322132 . _:b560322432 . _:b560322335 "2"^^ . _:b560322273 . _:b560322158 . . _:b560322435 . . _:b560322334 "2"^^ . _:b560322540 . _:b560322434 . _:b560322329 "2"^^ . _:b560322445 . . _:b560322328 "2"^^ . . _:b560322505 . _:b560322444 . . _:b560322331 "2"^^ . _:b560322479 . _:b33942563 . _:b560322447 . _:b560322330 "2"^^ . _:b560322527 . . _:b560322446 . . _:b560322341 "2"^^ . . _:b560322441 . _:b560322340 "2"^^ . _:b560322381 . _:b560322440 . _:b560322343 "2"^^ . _:b560322203 . . _:b560322443 . _:b560322342 "2"^^ . . _:b560322407 . _:b560322442 . _:b560322213 . _:b560322456 . _:b560322337 "2"^^ . _:b560322453 . _:b33942543 "The combination of crizotinib plus OSI-906 was confirmed to be synergistic using the Mix-Low method>>9<< (Supplementary Fig." . _:b560322336 "2"^^ . _:b560322452 . _:b560322339 "2"^^ . _:b560322439 . _:b560322197 . _:b560322455 . . _:b560322338 "2"^^ . . _:b560322434 . . _:b560322454 . _:b560322142 . _:b560322349 "2"^^ . _:b560322128 . _:b560322127 . . _:b560322405 . _:b560322449 . _:b560322348 "2"^^ . . . _:b560322448 . _:b560322351 "2"^^ . _:b560322451 . _:b560322350 "2"^^ . . _:b560322450 . . . _:b560322345 "2"^^ . . . _:b560322565 . . _:b560322461 . _:b560322570 . _:b560322344 "2"^^ . _:b560322564 . _:b560322274 . _:b560322460 . _:b560322347 "2"^^ . _:b560322377 . _:b560322567 . _:b560322463 . . _:b560322346 "2"^^ . . _:b560322566 . _:b560322462 . _:b560322357 "2"^^ . _:b560322382 . _:b560322561 . _:b560322410 . . _:b560322457 . _:b560322356 "2"^^ . _:b560322560 . _:b560322209 . _:b560322456 . _:b560322359 "2"^^ . _:b560322563 . . _:b560322459 . _:b560322358 "2"^^ . _:b560322562 . _:b560322458 . _:b560322353 "2"^^ . _:b560322125 . _:b560322573 . _:b560322224 . _:b560322469 . _:b560322352 "2"^^ . _:b560322572 . . _:b560322468 . _:b560322355 "2"^^ . _:b560322575 . . . _:b560322471 . . _:b560322354 "2"^^ . . _:b560322574 . _:b560322470 . _:b560322365 "2"^^ . _:b560322283 . _:b560322569 . . _:b560322123 . _:b560322465 . _:b560322364 "2"^^ . _:b560322440 . _:b560322568 . _:b560322206 . _:b33942560 . _:b560322464 . _:b560322367 "2"^^ . _:b560322259 . _:b560322571 . _:b560322208 . _:b560322467 . _:b560322299 . _:b560322160 . _:b560322366 "2"^^ . _:b560322570 . _:b560322466 . _:b560322361 "2"^^ . _:b560322227 . _:b560322581 . _:b560322477 . _:b560322360 "2"^^ . _:b560322580 . _:b560322585 . . _:b560322476 . _:b560322363 "2"^^ . . _:b560322583 . _:b560322386 . _:b560322479 . _:b560322362 "2"^^ . _:b560322582 . _:b560322074 . _:b560322478 . . _:b560322373 "2"^^ . . . _:b560322577 . _:b560322473 . . _:b560322372 "2"^^ . _:b560322576 . _:b560322472 . _:b560322375 "2"^^ . _:b560322579 . _:b560322475 . _:b560322374 "2"^^ . _:b560322578 . . _:b560322474 . _:b560322369 "2"^^ . . _:b560322485 . . _:b560322368 "2"^^ . . _:b560322484 . . _:b560322371 "2"^^ . . _:b560322487 . _:b560322370 "2"^^ . . _:b560322486 . . _:b33942570 "NanoString nCounter analysis of RNA isolated from formalin-fixed and paraffin embedded (FFPE) samples was performed as previously described>>23<<. The raw data were normalized to the nCounter system spike-in positive and negative controls in each sample." . _:b560322381 "2"^^ . _:b560322585 . _:b560322198 . _:b560322511 . _:b560322481 . _:b560322380 "2"^^ . _:b560322584 . . _:b560322480 . _:b560322383 "2"^^ . . _:b560322184 . _:b560322483 . . _:b560322382 "2"^^ . _:b560322482 . _:b560322377 "2"^^ . . _:b560322493 . _:b560322188 . _:b560322376 "2"^^ . _:b560322245 . _:b560322492 . _:b560322379 "2"^^ . _:b560322354 . _:b560322495 . _:b560322378 "2"^^ . _:b560322494 . _:b560322389 "2"^^ . _:b560322562 . _:b560322178 . _:b560322489 . _:b560322388 "2"^^ . _:b33942551 "IGFBP3 is known to block IGF-1 induced activation of IGF-1R16,>>17<<. Overall, these studies show that the IGF-1R signaling pathway is activated by multiple mechanisms in H3122 XR cells." . . . _:b560322488 . _:b560322391 "2"^^ . . _:b560322336 . _:b560322491 . _:b560322390 "2"^^ . _:b560322490 . _:b560322385 "2"^^ . _:b560322108 . _:b33942557 . _:b560322501 . _:b560322384 "2"^^ . _:b560322484 . _:b560322179 . _:b560322500 . _:b560322284 . _:b560322488 . _:b560322387 "2"^^ . . _:b560322503 . _:b560322386 "2"^^ . _:b560322100 . _:b560322502 . _:b560322397 "2"^^ . _:b560322461 . _:b33942565 . _:b560322497 . _:b560322300 . _:b560322396 "2"^^ . _:b560322207 . _:b560322496 . _:b560322399 "2"^^ . . _:b560322499 . _:b560322398 "2"^^ . _:b560322498 . _:b560322393 "2"^^ . . . _:b560322509 . _:b560322399 . _:b560322392 "2"^^ . _:b560322508 . _:b560322395 "2"^^ . . . _:b560322511 . _:b560322394 "2"^^ . . _:b560322458 . _:b560322510 . _:b560322405 "2"^^ . _:b560322368 . _:b560322505 . _:b560322404 "2"^^ . . _:b560322504 . _:b560322407 "2"^^ . . . _:b560322507 . _:b560322090 . _:b560322406 "2"^^ . _:b560322506 . _:b560322401 "2"^^ . . _:b33942554 "Previous studies have suggested that the IGF-1R pathway can drive EGFR inhibitor resistance19,>>20<<. We tested the efficacy of combined EGFR/IGF-1R inhibition in 4 different isogenic pairs of EGFR TKI- sensitive and -resistant cell lines21,22 (Supplementary Table 4)." . _:b560322517 . _:b560322172 . _:b560322400 "2"^^ . . . _:b560322516 . . _:b560322403 "2"^^ . _:b560322519 . _:b560322402 "2"^^ . _:b560322583 . _:b560322427 . . . _:b560322541 . _:b560322412 . _:b560322523 . _:b560322518 . _:b560322413 "2"^^ . . _:b560322442 . . _:b560322513 . _:b560322412 "2"^^ . . _:b560322512 . _:b560322415 "2"^^ . . _:b560322487 . _:b560322515 . _:b560322414 "2"^^ . _:b33942540 "Analysis of \u2018exceptional responders\u2019 has revealed important insights into drug sensitivity>>7<<. We describe a patient with ALK+ lung cancer who had an \u2018exceptional response\u2019 to an IGF-1R inhibitor prior to ALK TKI therapy." . _:b560322180 . . _:b560322514 . "10.1038%2Fnm.3667" . _:b560322409 "2"^^ . _:b560322319 . _:b560322525 . _:b560322400 . _:b560322408 "2"^^ . _:b560322524 . . _:b560322411 "2"^^ . _:b560322334 . . _:b560322527 . _:b560322410 "2"^^ . _:b560322165 . _:b560322526 . _:b560322421 "2"^^ . . _:b560322521 . _:b560322420 "2"^^ . _:b560322520 . _:b560322423 "2"^^ . _:b560322444 . . _:b560322523 . _:b33942560 "Our data may also in part explain the surprising 56% ORR for the \u2018second generation\u2019 ALK TKI, LDK-378, in patients with ALK+ lung cancer who had progressed on crizotinib>>24<<. Since responses to LDK-378 were observed in both patients with and without \u2018second-site\u2019 ALK mutations, the increased \u2018on-target\u2019 potency of LDK-378 towards ALK is alone not enough to explain all of the responses seen to this agent. We" . _:b560322422 "2"^^ . _:b560322522 . _:b560322417 "2"^^ . . _:b560322533 . _:b560322416 "2"^^ . _:b560322185 . _:b560322532 . _:b560322419 "2"^^ . _:b560322535 . _:b560322418 "2"^^ . . _:b560322534 . _:b560322429 "2"^^ . . _:b560322529 . . _:b560322428 "2"^^ . . . . _:b560322528 . . _:b560322431 "2"^^ . . _:b560322531 . . _:b560322430 "2"^^ . _:b560322110 . _:b560322530 . _:b560322425 "2"^^ . _:b560322302 . . _:b560322541 . _:b560322337 . _:b560322424 "2"^^ . . _:b560322540 . . . _:b560322427 "2"^^ . . _:b560322543 . _:b560322426 "2"^^ . _:b560322507 . _:b560322552 . _:b560322542 . _:b560322437 "2"^^ . . _:b560322546 . _:b560322537 . _:b560322436 "2"^^ . _:b560322426 . _:b560322536 . . _:b560322439 "2"^^ . . . . _:b560322539 . _:b33942561 . _:b560322438 "2"^^ . _:b560322538 . _:b560322433 "2"^^ . _:b560322549 . _:b33942558 "Interestingly, LDK-378 and the structurally related ALK inhibitor, TAE-684, can inhibit both ALK and IGF-1R in vitro>>25<<. We hypothesized that the efficacy of LDK-378 may be due to this drug's ability to simultaneously block both ALK and IGF-1R. LDK-378 was more potent than crizotinib in H3122 (Fig. 6a), STE-1 (Supplementary Fig. 7a), and H3122 XR cells" . _:b560322432 "2"^^ . _:b560322548 . _:b560322078 . _:b560322435 "2"^^ . _:b560322551 . _:b560322434 "2"^^ . _:b560322550 . _:b560322445 "2"^^ . . . _:b560322545 . _:b560322444 "2"^^ . _:b560322495 . _:b33942538 . _:b560322544 . . _:b560322447 "2"^^ . _:b33942541 . . . _:b560322436 . _:b560322547 . _:b560322446 "2"^^ . _:b560322546 . _:b560322113 . _:b560322441 "2"^^ . _:b560322453 . _:b560322557 . . _:b560322440 "2"^^ . _:b560322261 . _:b560322226 . . _:b560322460 . _:b560322556 . _:b560322443 "2"^^ . _:b560322141 . _:b33942559 . _:b560322432 . _:b560322559 . _:b560322442 "2"^^ . . . _:b560322558 . _:b560322453 "2"^^ . _:b33942561 "online methods" . _:b560322553 . _:b560322394 . _:b560322452 "2"^^ . . _:b560322552 . . _:b560322455 "2"^^ . _:b560322424 . _:b560322258 . _:b560322555 . _:b560322454 "2"^^ . . . _:b560322554 . _:b560322449 "2"^^ . _:b560322359 . _:b560322448 "2"^^ . _:b560322279 . _:b560322320 . . _:b560322451 "2"^^ . _:b560322155 . _:b560322450 "2"^^ . _:b560322514 . _:b560322294 . _:b560322461 "2"^^ . _:b560322332 . . _:b560322460 "2"^^ . _:b560322369 . _:b560322195 . . _:b560322547 . _:b560322210 . _:b560322463 "2"^^ . . _:b560322462 "2"^^ . . . . _:b560322457 "2"^^ . _:b33942539 . _:b560322456 "2"^^ . _:b560322211 . _:b33942562 "The human lung adenocarcinoma cell lines H3122 and H2228 have been described previously and were verified to harbor their reported genetic alterations by direct cDNA sequencing>>14<<. Derivation of the human lung adenocarcinoma cell line, STE-1, is described below. The human anaplastic lymphoma cell line, SUDHL-1, has been previously described26. The isogenic pairs of EGFR TKI sensitive and EGFR TKI resistant cell" . _:b560322459 "2"^^ . _:b560322458 "2"^^ . . _:b560322469 "2"^^ . . _:b560322468 "2"^^ . _:b560322536 . . _:b560322471 "2"^^ . _:b560322470 "2"^^ . . _:b560322465 "2"^^ . . . _:b560322464 "2"^^ . _:b560322230 . _:b560322467 "2"^^ . _:b33942565 "The reads were aligned to the Human Genome (UCSC hg19) using BWA>>27<<. The default arguments of BWA were applied to the alignment." . . _:b560322231 . _:b560322466 "2"^^ . _:b560322234 . . _:b560322477 "2"^^ . _:b560322268 . _:b560322121 . . _:b560322476 "2"^^ . _:b560322403 . . _:b560322173 . _:b560322479 "2"^^ . . _:b33942553 "Previous studies have suggested that the IGF-1R pathway can drive EGFR inhibitor resistance>>19<<,20. We tested the efficacy of combined EGFR/IGF-1R inhibition in 4 different isogenic pairs of EGFR TKI- sensitive and -resistant cell lines21,22 (Supplementary Table 4)." . . . _:b560322478 "2"^^ . _:b560322499 . . . _:b560322473 "2"^^ . _:b560322297 . _:b560322077 . _:b560322472 "2"^^ . . _:b560322076 . _:b560322475 "2"^^ . _:b560322079 . _:b560322474 "2"^^ . . _:b560322078 . _:b560322485 "2"^^ . _:b560322371 . _:b33942555 "We tested the efficacy of combined EGFR/IGF-1R inhibition in 4 different isogenic pairs of EGFR TKI- sensitive and -resistant cell lines21,>>22<< (Supplementary Table 4)." . _:b560322484 "2"^^ . . . _:b560322487 "2"^^ . _:b560322075 . . _:b560322486 "2"^^ . _:b560322074 . _:b560322325 . _:b560322481 "2"^^ . _:b560322085 . _:b560322480 "2"^^ . _:b560322106 . _:b560322084 . _:b560322483 "2"^^ . _:b33942555 . . . _:b560322087 . _:b560322129 . _:b560322482 "2"^^ . . _:b560322107 . _:b33942552 . _:b560322086 . _:b560322493 "2"^^ . _:b560322076 . _:b560322081 . . _:b560322492 "2"^^ . . . _:b560322080 . _:b560322495 "2"^^ . _:b560322083 . _:b560322494 "2"^^ . _:b560322082 . _:b560322464 . . _:b560322489 "2"^^ . _:b560322379 . _:b560322093 . _:b560322554 . _:b560322488 "2"^^ . _:b560322092 . . . _:b560322491 "2"^^ . . _:b560322411 . _:b560322095 . . _:b560322490 "2"^^ . . _:b560322099 . _:b560322094 . _:b560322239 . _:b560322501 "2"^^ . . _:b560322089 . _:b560322494 . _:b560322174 . _:b560322500 "2"^^ . _:b560322374 . . . . _:b560322088 . _:b560322352 . _:b560322503 "2"^^ . . _:b560322091 . . . _:b560322502 "2"^^ . . _:b560322090 . _:b560322497 "2"^^ . . _:b560322101 . _:b560322496 "2"^^ . _:b33942564 . _:b560322100 . _:b560322499 "2"^^ . _:b560322103 . _:b560322498 "2"^^ . _:b560322102 . . . _:b560322509 "2"^^ . _:b560322159 . _:b560322097 . _:b560322508 "2"^^ . . _:b560322096 . _:b560322511 "2"^^ . _:b560322433 . . _:b560322408 . _:b560322099 . . _:b560322510 "2"^^ . _:b560322339 . _:b560322098 . _:b560322191 . _:b560322505 "2"^^ . . . _:b560322109 . _:b560322138 . _:b560322504 "2"^^ . . _:b560322108 . _:b560322507 "2"^^ . . _:b560322111 . . _:b560322506 "2"^^ . _:b560322243 . _:b33942561 _:b33942562 . _:b33942561 _:b33942563 . . _:b560322110 . _:b33942561 _:b33942564 . _:b560322517 "2"^^ . _:b33942561 _:b33942565 . _:b33942561 _:b33942566 . . _:b33942561 _:b33942567 . _:b560322105 . _:b33942561 _:b33942568 . _:b560322516 "2"^^ . _:b560322181 . _:b33942561 _:b33942569 . . _:b33942561 _:b33942570 . _:b33942561 _:b33942571 . _:b560322104 . _:b33942561 _:b33942572 . _:b560322519 "2"^^ . _:b33942561 _:b33942573 . _:b560322503 . _:b560322107 . _:b560322324 . _:b560322266 . _:b560322217 . _:b560322518 "2"^^ . _:b560322106 . _:b560322513 "2"^^ . _:b560322117 . _:b560322512 "2"^^ . . _:b560322116 . _:b560322550 . _:b560322262 . _:b560322305 . _:b560322515 "2"^^ . _:b560322119 . . _:b560322542 . _:b560322514 "2"^^ . _:b560322118 . . _:b33942552 "Apoptosis was also enhanced in H3122 XR cells treated with X-376 and the IGF-1R TKI, AEW->>54118<< (Fig. 4f). In accord with these data, combination treatment with ALK and IGF-1R inhibitors in H3122 XR cells inhibited AKT phosphorylation to a greater extent than either inhibitor alone (Fig. 4g). The addition of OSI-906 also partially" . _:b560322525 "2"^^ . _:b560322248 . . _:b560322113 . . _:b560322524 "2"^^ . _:b560322093 . _:b560322112 . _:b560322116 . _:b560322527 "2"^^ . _:b560322140 . . _:b560322251 . _:b560322115 . _:b560322526 "2"^^ . _:b560322114 . _:b560322521 "2"^^ . _:b560322125 . _:b560322520 "2"^^ . _:b560322124 . _:b560322454 . _:b560322523 "2"^^ . . _:b560322127 . _:b560322215 . _:b560322522 "2"^^ . _:b560322126 . _:b560322533 "2"^^ . _:b560322121 . _:b560322347 . _:b560322532 "2"^^ . _:b560322271 . _:b560322120 . _:b560322535 "2"^^ . _:b560322560 . _:b560322123 . _:b560322534 "2"^^ . . _:b560322122 . . _:b560322529 "2"^^ . _:b560322164 . . _:b560322133 . _:b560322528 "2"^^ . _:b560322080 . _:b560322083 . . _:b560322077 . _:b560322132 . _:b560322531 "2"^^ . _:b560322307 . _:b560322135 . _:b560322293 . _:b560322530 "2"^^ . _:b560322134 . . _:b560322541 "2"^^ . _:b560322395 . . _:b560322508 . _:b560322129 . _:b560322540 "2"^^ . _:b560322128 . . _:b560322543 "2"^^ . . _:b560322131 . _:b560322542 "2"^^ . . _:b560322130 . _:b560322391 . _:b560322537 "2"^^ . _:b560322141 . _:b33942559 _:b33942560 . _:b560322536 "2"^^ . _:b560322445 . _:b560322353 . _:b560322140 . _:b560322539 "2"^^ . . _:b560322143 . _:b33942538 _:b33942540 . _:b560322538 "2"^^ . _:b33942541 _:b33942544 . _:b33942541 _:b33942545 . _:b33942541 _:b33942546 . _:b33942541 _:b33942547 . _:b560322142 . _:b33942541 _:b33942548 . _:b560322549 "2"^^ . _:b33942541 _:b33942549 . _:b33942541 _:b33942550 . _:b33942538 _:b33942539 . _:b560322137 . _:b33942541 _:b33942551 . _:b33942541 _:b33942552 . _:b560322548 "2"^^ . _:b33942541 _:b33942553 . _:b33942541 _:b33942554 . . _:b560322136 . _:b33942541 _:b33942555 . _:b33942541 _:b33942556 . _:b560322551 "2"^^ . _:b33942541 _:b33942557 . _:b33942551 . _:b560322149 . _:b33942541 _:b33942558 . _:b560322312 . _:b560322139 . _:b560322550 "2"^^ . _:b560322138 . _:b560322457 . . _:b560322545 "2"^^ . . . _:b560322149 . _:b560322574 . _:b560322544 "2"^^ . . _:b560322148 . _:b560322547 "2"^^ . _:b33942541 _:b33942542 . _:b33942541 _:b33942543 . _:b560322151 . _:b560322546 "2"^^ . _:b560322441 . . _:b560322150 . _:b560322378 . _:b560322557 "2"^^ . _:b560322578 . _:b560322145 . _:b560322556 "2"^^ . _:b560322144 . _:b560322323 . _:b560322559 "2"^^ . . _:b560322221 . _:b560322147 . _:b560322558 "2"^^ . _:b560322348 . _:b33942571 . . _:b560322146 . . _:b560322553 "2"^^ . _:b560322157 . . _:b560322552 "2"^^ . _:b560322156 . . _:b560322555 "2"^^ . . _:b560322565 "2"^^ . _:b560322159 . _:b560322554 "2"^^ . _:b560322564 "2"^^ . _:b560322158 . _:b33942542 . _:b560322567 "2"^^ . _:b560322153 . _:b560322152 . _:b560322270 . _:b560322566 "2"^^ . _:b560322136 . _:b560322152 . _:b560322561 "2"^^ . _:b560322155 . . _:b560322560 "2"^^ . _:b560322328 . _:b560322330 . _:b560322154 . _:b560322350 . . _:b560322563 "2"^^ . _:b560322165 . _:b560322563 . _:b560322562 "2"^^ . _:b560322164 . _:b560322573 "2"^^ . _:b560322565 . _:b560322167 . _:b560322250 . _:b560322201 . _:b560322572 "2"^^ . . _:b560322166 . _:b33942572 . _:b560322467 . _:b560322575 "2"^^ . _:b560322161 . _:b560322574 "2"^^ . _:b560322569 . _:b560322160 . _:b560322569 "2"^^ . _:b560322163 . _:b560322504 . _:b560322519 . _:b560322568 "2"^^ . . _:b560322162 . _:b560322214 . . _:b560322571 "2"^^ . _:b560322415 . _:b560322173 . . _:b560322570 "2"^^ . _:b560322172 . _:b560322580 . _:b560322421 . _:b560322581 "2"^^ . _:b560322548 . _:b560322175 . _:b560322580 "2"^^ . _:b560322117 . _:b560322174 . _:b33942549 . _:b560322583 "2"^^ . _:b560322169 . . _:b560322582 "2"^^ . _:b560322168 . . _:b560322577 "2"^^ . _:b560322171 . _:b560322576 "2"^^ . . _:b560322170 . _:b560322584 . _:b560322579 "2"^^ . . _:b560322181 . _:b560322269 . . _:b560322578 "2"^^ . _:b560322491 . _:b560322481 . _:b560322180 . _:b560322183 . _:b560322171 . _:b560322102 . _:b560322182 . _:b560322478 . . _:b560322177 . _:b560322176 . _:b560322329 . _:b560322585 "2"^^ . _:b560322222 . . _:b560322179 . _:b560322584 "2"^^ . _:b560322178 . . _:b560322189 . _:b560322188 . . _:b560322191 . _:b560322311 . . _:b560322190 . . _:b33942547 "We also validated that this interaction occurs in vivo using tissue from two different EML4-ALK E13;A20 transgenic mice>>13<< (Fig. 3d)." . _:b560322185 . _:b560322470 . _:b560322480 . _:b560322521 . . _:b560322509 . _:b560322184 . . _:b560322194 . . _:b560322187 . _:b560322342 . _:b560322322 . _:b560322186 . . . _:b560322197 . . _:b560322196 . . _:b560322524 . _:b560322199 . _:b560322143 . . _:b560322431 . _:b560322198 . . . _:b560322170 . _:b560322193 . . . _:b560322310 . _:b560322192 . _:b560322220 . _:b560322195 . _:b560322473 . . _:b560322194 . . . _:b560322205 . . . . _:b560322204 . _:b560322207 . . _:b560322206 . . _:b560322264 . . _:b560322139 . _:b560322435 . _:b560322201 . _:b560322200 . . . _:b560322203 . _:b560322571 . _:b560322202 . . . . _:b560322213 . _:b560322232 . _:b560322413 . _:b560322212 . . . . _:b560322215 . . . . . _:b560322214 . . _:b560322446 . . . _:b33942544 "OSI-906 has no off-target activity against ALK at the doses used in these experiments>>10<<." . _:b560322209 . _:b560322186 . _:b560322373 . _:b560322208 . _:b560322211 . . _:b560322210 . _:b560322119 . _:b560322253 . _:b560322526 . . _:b560322233 . _:b560322221 . _:b560322225 . _:b560322573 . _:b560322220 . . _:b560322414 . . _:b560322223 . _:b33942547 . _:b560322568 . _:b560322308 . _:b560322222 . _:b560322360 . . _:b560322217 . _:b560322216 . _:b560322219 . _:b560322218 . _:b560322229 . _:b560322506 . _:b560322419 . _:b560322387 . _:b560322124 . . _:b560322576 . _:b560322228 . _:b560322228 . _:b560322249 . _:b560322231 . _:b560322462 . . _:b560322230 . . _:b560322225 . . _:b560322224 . _:b33942566 "After the alignment, we ran the software SAMtools >>28<< to convert the alignment files to a sorted, indexed binary alignment map (BAM) format." . _:b33942567 . _:b560322227 . _:b33942556 . _:b33942540 . . _:b560322226 . _:b560322237 . _:b33942542 "Previous studies have reported a 0% response rate for ALK+ lung cancer patients treated with erlotinib alone>>8<<. Thus, we hypothesized that in this patient, either the combination of erlotinib plus the IGF-1R inhibitor was synergistic against ALK+ lung cancer, or the IGF-1R inhibitor alone was somehow responsible for the tumor response." . . _:b560322236 . _:b560322327 . . _:b560322239 . _:b560322535 . _:b560322238 .