_:b2578109 "role of her3 in breast cancer drug resistance" . . _:b357847282 . _:b357847293 . _:b357847200 . _:b357847292 . . _:b357847295 . _:b357847294 . _:b357847110 . _:b357847289 . . _:b357847288 . _:b357847291 . _:b357847429 . . _:b357847290 . . . . . . . . . . . _:b357847318 . _:b357847385 . . _:b357847265 . . _:b2578095 "Tumours arising in mice due to the transgenic overexpression of Neu are also characterised by increased expression and phosphorylation of HER3 (Siegel et al, >>1999<<). Increased expression of HER3 synergistically increases the transforming potency of HER2 (Alimandi et al, 1995). Conversely, loss of HER3 abolishes the transforming ability of HER2, and indeed HER3 is in fact an obligate partner in" . . _:b357847250 . _:b357847241 . _:b357847169 . _:b357847308 . _:b2578110 "autophosphorylation of EGFR and HER2 in these tumour cells; however, the transphosphorylation of HER3 is only transiently suppressed and HER3 ultimately escapes inhibition by TKIs in HER2-overexpressing tumour cells (Sergina et al, >>2007<<). The consequence of HER3 resistance is PI3K/Akt pathway resistance, tumour survival, and escape from the proapoptotic consequences of the loss of oncogenic HER2 signalling." . _:b357847178 . _:b357847326 . . _:b357847229 . . . _:b357847307 . _:b357847246 . _:b2578106 "targeting her proteins in breast cancer" . _:b357847401 . _:b357847347 . _:b2578099 "This function is directly mediated through HER3, which unlike EGFR and HER2, has six tyrosine containing binding sites for p85, the regulatory subunit of PI3K (Prigent and Gullick, 1994; Soltoff et al, >>1994<<). The growth factor activation of PI3K and Akt by HER2 is mediated through the tyrosine phosphorylation of HER3 (Soltoff et al, 1994). Although immunohistochemical reagents are currently unable to directly assay HER3 activity in fixed" . _:b357847194 . . _:b357847158 . _:b357847217 . _:b357847300 . . _:b357847389 . _:b357847131 . _:b357847416 . . _:b357847183 . . . . _:b357847161 . . _:b357847172 . _:b2578096 "Increased expression of HER3 synergistically increases the transforming potency of HER2 (Alimandi et al, >>1995<<). Conversely, loss of HER3 abolishes the transforming ability of HER2, and indeed HER3 is in fact an obligate partner in HER2-mediated transformation (Holbro et al, 2003)." . _:b357847109 . . . . _:b357847304 . _:b357847213 . _:b357847366 . . . _:b357847432 . _:b357847184 . _:b357847315 . _:b357847254 . . . _:b357847271 . _:b357847288 . . _:b357847187 . _:b357847137 . _:b357847299 . _:b357847212 . _:b357847133 . . . _:b357847130 . _:b357847355 . . . . _:b357847384 . _:b357847291 . _:b357847238 . . . . . _:b2578090 . _:b357847224 . . . _:b357847298 . _:b357847111 . _:b357847327 . _:b357847290 . . . . _:b2578092 "induced by the doxycycline induction of Neu overexpression, withdrawal of the Neu oncogene by cessation of doxycycline therapy results in complete regression of the mammary tumours and its associated tumour metastases (Moody et al, >>2002<<). While the simplicity of each of these model systems understates the complexity of HER2-overexpressing human breast cancers, it makes a compelling case that HER2 plays a dominant role in causing and maintaining the transformed phenotype," . . . _:b357847377 . _:b357847350 . . _:b357847144 . _:b357847251 . . _:b2578083 "and neck cancers, activated by amplification and/or mutation in approximately 50% of gliomas, activated by mutation in about 10\u201315% of non-small cell lung cancers (NSCLC) in the west, and 30\u201350% of NSCLCs in Asia (Frederick et al, >>2000<<; Riely et al, 2006). Amplification and overexpression of HER2 is seen in about 25\u201330% of breast cancers and occasionally in other cancers (Slamon et al, 1989)." . . _:b2578111 "This study also showed that HER2-driven tumours ultimately cannot escape the total inactivation of HER2 (Sergina et al, >>2007<<), leaving hope that more potent TKIs or higher doses of TKIs may yet show significant activity in this disease." . . . _:b357847296 . . . _:b357847149 . . _:b357847237 . _:b357847152 . _:b357847153 . _:b357847227 . _:b357847154 . _:b357847155 . _:b357847156 . _:b357847157 . _:b357847158 . _:b357847159 . _:b357847166 . _:b357847160 . _:b357847301 . _:b357847161 . _:b357847273 . _:b357847162 . _:b357847207 . . _:b357847163 . . _:b357847164 . _:b357847300 . _:b357847165 . _:b357847166 . . _:b357847167 . _:b2578114 . . _:b357847136 . _:b357847303 . _:b357847137 . _:b357847138 . . _:b357847139 . _:b357847394 . _:b357847140 . _:b357847302 . _:b357847141 . _:b357847142 . _:b357847143 . _:b357847144 . _:b357847096 . _:b357847175 . _:b357847297 . _:b357847145 . _:b357847146 . _:b357847147 . _:b357847148 . _:b2578092 . _:b357847296 . . _:b357847149 . _:b357847150 . _:b357847216 . _:b357847151 . _:b357847120 . _:b357847299 . _:b357847121 . _:b357847122 . . _:b357847123 . _:b357847124 . _:b357847298 . _:b357847125 . _:b357847126 . _:b357847127 . _:b357847297 . _:b357847128 . _:b357847346 . _:b357847309 . _:b357847129 . . _:b357847130 . _:b357847131 . _:b357847132 . _:b357847308 . _:b357847133 . . _:b357847134 . _:b357847135 . _:b357847104 . _:b357847311 . _:b357847105 . _:b357847106 . _:b357847107 . _:b357847108 . _:b357847310 . _:b357847193 . _:b357847109 . _:b357847263 . _:b357847242 . _:b357847110 . _:b357847111 . . _:b357847112 . _:b357847305 . _:b357847113 . _:b357847114 . _:b357847115 . _:b357847116 . _:b357847304 . _:b357847117 . _:b357847118 . . _:b357847119 . _:b357847240 . _:b357847104 . _:b357847307 . _:b357847306 . _:b357847096 . _:b357847317 . _:b357847097 . _:b2578086 "contrast to the other family members, the current evidence suggests that HER4 mediates antiproliferative effects; and consistent with this, HER4 overactivity does not appear to play a major role in cancer pathogenesis (Sartor et al, >>2001<<; Naresh et al, 2006)." . . _:b357847098 . _:b357847099 . _:b357847100 . _:b357847316 . . _:b357847101 . _:b357847102 . _:b2578125 "This has been demonstrated through the restoration of TKI sensitivity by inducible re-expression of PTEN in PTEN-null tumour cells (She et al, >>2003<<). Since the inactivation of PTEN activates Akt signalling at a point downstream of HER3, a role for HER3 in mediating drug resistance in PTEN-deleted tumours may be redundant. The role of HER3 in gliomagenesis and in response and" . _:b357847103 . _:b357847319 . . _:b357847318 . . . _:b357847313 . . _:b357847312 . _:b357847380 . _:b357847315 . _:b357847338 . . . _:b357847314 . _:b357847325 . _:b357847368 . _:b357847358 . . _:b357847324 . _:b357847327 . . _:b357847326 . . . _:b2578098 "This function is directly mediated through HER3, which unlike EGFR and HER2, has six tyrosine containing binding sites for p85, the regulatory subunit of PI3K (Prigent and Gullick, >>1994<<; Soltoff et al, 1994)." . . _:b357847321 . _:b357847148 . . . _:b357847320 . . _:b357847323 . _:b357847163 . _:b357847280 . _:b357847281 . _:b357847333 . _:b357847282 . _:b357847283 . _:b357847284 . _:b357847322 . . _:b357847285 . _:b357847286 . _:b357847287 . _:b357847288 . _:b357847333 . _:b357847289 . _:b357847407 . _:b357847290 . . . _:b357847303 . _:b357847291 . _:b2578110 . _:b357847292 . _:b357847332 . _:b357847293 . _:b357847294 . _:b357847208 . _:b357847295 . _:b2578111 . _:b357847264 . _:b357847335 . _:b357847265 . _:b357847266 . _:b357847267 . _:b357847268 . _:b357847334 . _:b357847269 . _:b357847270 . _:b357847271 . _:b357847272 . _:b357847438 . _:b357847329 . _:b357847273 . _:b357847274 . _:b357847345 . _:b357847275 . _:b2578094 . _:b357847276 . _:b357847328 . _:b357847277 . _:b357847278 . . _:b357847287 . _:b357847279 . _:b357847248 . _:b357847331 . . _:b357847249 . _:b357847250 . _:b357847251 . _:b357847252 . _:b357847330 . _:b357847253 . _:b357847254 . _:b357847255 . _:b357847256 . _:b357847341 . _:b357847257 . _:b357847258 . _:b357847259 . _:b357847260 . _:b357847340 . _:b357847261 . _:b357847262 . _:b357847263 . _:b357847232 . _:b357847343 . _:b357847233 . . _:b357847234 . _:b357847235 . _:b357847236 . _:b357847417 . _:b357847342 . _:b357847237 . _:b357847238 . _:b357847239 . _:b357847353 . _:b357847240 . _:b357847337 . _:b357847241 . _:b357847242 . _:b357847243 . _:b357847244 . _:b357847336 . . _:b357847245 . _:b357847426 . _:b357847246 . _:b357847247 . _:b357847216 . _:b357847339 . _:b357847217 . _:b357847218 . _:b2578124 . _:b357847414 . _:b357847280 . _:b357847219 . _:b357847220 . _:b357847338 . _:b357847221 . . _:b357847396 . _:b357847222 . _:b357847223 . _:b357847224 . _:b2578089 . _:b357847349 . _:b357847225 . _:b357847226 . _:b357847227 . _:b357847228 . _:b357847348 . _:b357847229 . _:b357847230 . _:b357847231 . _:b357847200 . _:b357847351 . _:b357847201 . _:b357847202 . _:b357847203 . . _:b357847204 . _:b357847350 . _:b357847205 . . _:b357847206 . . _:b357847207 . _:b357847208 . _:b357847345 . _:b357847209 . _:b357847210 . _:b357847211 . _:b357847212 . _:b2578108 . _:b357847344 . _:b357847213 . _:b357847214 . _:b2578101 "Although immunohistochemical reagents are currently unable to directly assay HER3 activity in fixed tissues from clinical studies, the activation of HER3 in the mouse model of HER2-induced tumours is established (Siegel et al, >>1999<<). Akt activity, however, can be assayed in clinical samples, and the clinical data indeed shows frequent activation of Akt in HER2-expressing tumours (Tokunaga et al, 2006a). The role of Akt as a critical proliferative and antiapoptotic" . _:b357847215 . _:b357847184 . _:b357847347 . . _:b357847185 . _:b357847186 . _:b357847187 . _:b357847188 . _:b357847346 . _:b357847189 . _:b357847190 . _:b357847191 . _:b357847192 . _:b357847357 . _:b357847193 . _:b357847194 . _:b357847195 . _:b357847196 . _:b357847356 . _:b357847197 . _:b357847198 . _:b357847420 . _:b357847199 . _:b357847168 . _:b357847359 . _:b357847169 . _:b357847170 . _:b357847440 . _:b357847171 . _:b357847172 . _:b357847358 . . _:b357847173 . _:b357847174 . _:b357847175 . _:b2578087 "family members, the current evidence suggests that HER4 mediates antiproliferative effects; and consistent with this, HER4 overactivity does not appear to play a major role in cancer pathogenesis (Sartor et al, 2001; Naresh et al, >>2006<<)." . . . _:b357847176 . _:b357847353 . _:b357847177 . _:b357847352 . _:b357847178 . _:b357847179 . _:b357847180 . _:b357847352 . _:b357847181 . _:b357847182 . _:b357847183 . _:b357847408 . _:b357847355 . _:b357847409 . _:b357847410 . _:b357847411 . _:b357847412 . _:b357847354 . _:b357847413 . _:b357847414 . _:b357847415 . _:b2578081 . _:b357847416 . _:b357847413 . _:b357847365 . _:b357847417 . _:b357847418 . _:b357847145 . _:b357847419 . . _:b357847420 . _:b357847364 . _:b357847421 . _:b357847422 . _:b2578088 . _:b357847232 . _:b357847354 . _:b357847423 . _:b357847392 . _:b357847367 . _:b357847247 . _:b357847393 . _:b357847394 . _:b357847395 . _:b2578093 . _:b357847396 . _:b357847366 . _:b357847397 . _:b357847398 . _:b357847399 . _:b357847400 . _:b357847361 . _:b357847401 . _:b357847168 . _:b357847402 . _:b357847403 . _:b357847301 . _:b357847404 . _:b357847360 . _:b357847405 . _:b357847209 . _:b357847406 . _:b2578104 . _:b357847407 . _:b357847405 . . _:b357847376 . _:b357847363 . _:b2578106 . _:b357847377 . _:b2578083 . _:b357847378 . _:b357847268 . . _:b2578109 . _:b357847379 . _:b357847155 . _:b357847362 . . _:b357847380 . _:b357847381 . _:b357847382 . _:b2578115 . _:b357847383 . _:b357847384 . _:b357847373 . _:b357847385 . _:b357847386 . _:b357847331 . _:b357847387 . . _:b357847372 . _:b357847132 . _:b357847388 . _:b357847389 . _:b357847390 . _:b357847164 . . _:b357847391 . _:b357847360 . _:b357847375 . _:b357847361 . _:b357847362 . . _:b357847363 . _:b357847364 . _:b357847374 . _:b357847365 . . _:b357847366 . _:b357847367 . . _:b357847368 . _:b357847369 . . _:b357847369 . _:b357847370 . . _:b357847371 . _:b357847340 . _:b357847372 . _:b357847368 . _:b357847373 . _:b357847374 . _:b357847375 . _:b357847344 . _:b357847371 . . _:b357847345 . _:b357847346 . _:b357847347 . _:b357847348 . _:b357847370 . _:b357847349 . _:b357847350 . _:b357847351 . _:b357847352 . _:b357847381 . _:b357847353 . _:b357847354 . _:b357847355 . _:b357847356 . _:b357847380 . _:b357847357 . _:b357847358 . _:b2578100 . _:b357847409 . _:b357847359 . _:b357847328 . _:b357847383 . _:b357847329 . _:b357847314 . _:b357847330 . _:b357847331 . _:b357847243 . . . _:b357847419 . _:b357847382 . . . _:b357847332 . _:b357847333 . . _:b357847334 . _:b357847335 . _:b357847336 . _:b357847377 . _:b357847337 . . _:b357847338 . _:b357847339 . _:b357847340 . _:b357847376 . _:b357847341 . _:b357847342 . . . _:b357847343 . . _:b357847379 . . _:b357847312 . _:b357847313 . _:b357847314 . _:b357847315 . _:b357847316 . _:b357847378 . _:b357847317 . _:b357847318 . _:b2578112 . _:b357847319 . _:b357847320 . _:b357847389 . _:b357847321 . _:b357847322 . _:b2578099 . _:b357847323 . _:b357847402 . _:b357847324 . _:b357847388 . _:b357847325 . _:b357847326 . . _:b357847327 . _:b2578121 . _:b357847296 . _:b357847391 . _:b357847297 . _:b357847298 . _:b357847299 . _:b357847300 . _:b357847390 . . _:b357847301 . _:b357847302 . _:b357847303 . _:b357847304 . _:b357847385 . _:b357847305 . _:b357847306 . _:b357847307 . _:b357847308 . _:b357847384 . _:b357847309 . _:b357847310 . _:b357847311 . _:b357847387 . . _:b2578094 "HER3 is frequently overexpressed in breast cancers with EGFR or HER2 overexpression (Naidu et al, >>1998<<). Tumours arising in mice due to the transgenic overexpression of Neu are also characterised by increased expression and phosphorylation of HER3 (Siegel et al, 1999). Increased expression of HER3 synergistically increases the transforming" . _:b357847386 . _:b357847376 . _:b357847397 . . _:b357847396 . . . _:b357847399 . _:b357847398 . _:b357847283 . _:b357847393 . . _:b357847392 . . _:b357847395 . . _:b357847392 . _:b357847394 . _:b357847154 . _:b357847274 . _:b357847405 . _:b357847404 . . . _:b357847407 . . . _:b357847406 . . _:b2578097 "Conversely, loss of HER3 abolishes the transforming ability of HER2, and indeed HER3 is in fact an obligate partner in HER2-mediated transformation (Holbro et al, >>2003<<)." . _:b357847278 . _:b357847401 . _:b357847351 . _:b2578118 "of TKI-sensitive lung cancers inactivates HER3 signalling and downstream PI3K/Akt signalling, but HER3 signalling in TKI-resistant lung cancers appears to be uncoupled from EGFR and resistant to inactivation by TKIs (Engelman et al, >>2005<<). The development of the EGFR T790M mutation in lung cancers confers drug resistance and is associated with persistent activation of HER3/PI3K/Akt signalling (Engelman et al, 2006)." . _:b357847399 . _:b357847400 . _:b357847196 . _:b357847403 . _:b357847402 . _:b357847413 . _:b357847348 . _:b357847412 . . _:b357847415 . _:b357847122 . _:b357847306 . _:b357847414 . _:b357847409 . _:b357847408 . _:b357847440 . _:b357847411 . . _:b357847410 . _:b357847293 . _:b357847373 . _:b357847421 . . . _:b357847420 . _:b357847424 . _:b357847423 . _:b357847387 . _:b357847425 . _:b357847426 . _:b357847427 . _:b357847244 . _:b357847422 . _:b357847428 . _:b357847429 . _:b357847430 . _:b357847431 . _:b357847432 . _:b357847417 . _:b357847433 . _:b357847434 . _:b357847435 . _:b357847436 . _:b357847416 . _:b357847437 . . _:b357847438 . _:b357847439 . _:b357847419 . _:b357847192 . . . _:b357847418 . _:b357847150 . _:b357847429 . . _:b357847428 . _:b357847431 . _:b357847138 . _:b357847370 . _:b357847430 . . _:b357847260 . _:b357847425 . _:b2578093 "mechanism of her2 tumorigenesis: the role of her3" . _:b357847215 . _:b357847424 . . _:b357847171 . _:b357847427 . _:b357847437 . _:b357847220 . _:b357847426 . _:b357847437 . _:b2578095 . _:b357847436 . _:b357847439 . . _:b2578084 "activated by amplification and/or mutation in approximately 50% of gliomas, activated by mutation in about 10\u201315% of non-small cell lung cancers (NSCLC) in the west, and 30\u201350% of NSCLCs in Asia (Frederick et al, 2000; Riely et al, >>2006<<). Amplification and overexpression of HER2 is seen in about 25\u201330% of breast cancers and occasionally in other cancers (Slamon et al, 1989)." . _:b357847100 . _:b357847438 . _:b2578104 "targeting her proteins" . _:b2578103 . _:b357847135 . _:b357847433 . . _:b357847339 . _:b357847189 . _:b357847432 . . . . _:b2578105 . _:b357847435 . _:b357847262 . . _:b357847434 . _:b357847179 . _:b357847173 . _:b357847272 . _:b357847415 . _:b357847167 . _:b357847418 . _:b357847103 "11"^^ . _:b357847393 . _:b357847102 "11"^^ . _:b357847096 "20"^^ . _:b357847097 "17"^^ . . _:b357847098 "15"^^ . _:b357847101 "11"^^ . _:b357847099 "14"^^ . _:b357847100 "11"^^ . _:b357847180 . _:b357847203 . _:b357847440 . . . _:b357847431 . _:b357847408 . _:b357847110 "9"^^ . _:b357847114 . _:b357847111 "9"^^ . _:b357847117 . _:b357847357 . _:b357847108 "9"^^ . . _:b357847363 . _:b357847109 "9"^^ . _:b357847129 . _:b357847107 "10"^^ . _:b357847198 . _:b357847106 "10"^^ . _:b357847362 . . . . _:b357847105 "10"^^ . _:b357847292 . . _:b357847104 "10"^^ . _:b357847134 . _:b357847118 "7"^^ . . _:b357847176 . _:b357847119 "7"^^ . _:b357847341 . . _:b2578101 . _:b357847116 "7"^^ . _:b357847325 . _:b357847410 . _:b357847117 "7"^^ . _:b357847321 . . _:b2578116 . _:b357847114 "8"^^ . _:b2578125 . _:b357847372 . . . _:b357847115 "8"^^ . . . _:b357847112 "9"^^ . _:b357847337 . _:b357847113 "8"^^ . _:b357847211 . _:b357847126 "6"^^ . _:b2578113 "The broad testing of EGFR-selective TKIs in cancers revealed a small subset of highly responsive lung cancer patients (Fukuoka et al, >>2003<<). Subsequent studies have identified this subset as patients with cancers driven by mutationally activated EGFR (Lynch et al, 2004)." . _:b2578091 "Knockdown of HER2 in HER2-overexpressing cancer cells induces apoptotic cell death (Roh et al, >>2000<<). In mouse models, wherein metastatic mammary carcinomas are induced by the doxycycline induction of Neu overexpression, withdrawal of the Neu oncogene by cessation of doxycycline therapy results in complete regression of the mammary" . _:b357847127 "6"^^ . _:b357847312 . _:b357847124 "6"^^ . . _:b357847294 . _:b357847125 "6"^^ . . _:b357847162 . _:b357847122 "7"^^ . . _:b357847123 "6"^^ . _:b357847255 . . . _:b357847120 "7"^^ . _:b357847121 "7"^^ . _:b2578082 "the HER2-HER3 heterodimer is a highly functional signalling unit and constitutes the most active signalling dimer in this family, exemplifying the role of complimentary functions in this complex receptor family (Tzahar et al, >>1996<<)." . _:b357847134 "6"^^ . . _:b357847317 . _:b357847132 "6"^^ . . _:b357847135 "5"^^ . _:b357847133 "6"^^ . . _:b357847130 "6"^^ . . _:b357847156 . _:b357847131 "6"^^ . _:b357847356 . . _:b357847128 "6"^^ . _:b357847129 "6"^^ . _:b357847152 . _:b2578118 . _:b357847230 . _:b357847141 "5"^^ . _:b357847342 . _:b357847124 . _:b357847140 "5"^^ . _:b357847143 "5"^^ . _:b357847127 . _:b2578117 . _:b357847142 "5"^^ . _:b357847137 "5"^^ . _:b357847125 . _:b357847136 "5"^^ . _:b357847361 . _:b357847139 "5"^^ . . _:b2578107 . _:b357847138 "5"^^ . _:b357847286 . _:b357847149 "5"^^ . _:b357847264 . _:b357847148 "5"^^ . _:b357847151 "5"^^ . _:b357847343 . . _:b357847430 . _:b357847150 "5"^^ . _:b357847145 "5"^^ . . _:b357847144 "5"^^ . . _:b357847147 "5"^^ . . . _:b357847146 "5"^^ . _:b357847157 "4"^^ . . _:b357847206 . _:b357847210 . _:b357847156 "4"^^ . _:b357847411 . _:b357847201 . _:b357847159 "4"^^ . _:b357847231 . _:b357847147 . _:b357847158 "4"^^ . _:b357847153 "5"^^ . _:b357847152 "5"^^ . _:b357847155 "4"^^ . _:b357847154 "5"^^ . . . _:b357847165 "4"^^ . _:b357847105 . . _:b357847164 "4"^^ . _:b357847167 "4"^^ . _:b357847267 . _:b357847166 "4"^^ . . _:b357847423 . _:b357847143 . . _:b357847118 . _:b357847161 "4"^^ . . _:b357847369 . _:b357847160 "4"^^ . _:b357847163 "4"^^ . _:b357847374 . _:b357847436 . _:b357847162 "4"^^ . _:b357847173 "4"^^ . . . _:b357847172 "4"^^ . . _:b357847175 "4"^^ . . _:b357847174 "4"^^ . _:b2578084 . . _:b357847169 "4"^^ . _:b2578085 . _:b357847168 "4"^^ . _:b2578086 . _:b357847119 . _:b357847116 . _:b357847171 "4"^^ . _:b2578087 . _:b357847367 . _:b2578097 . _:b357847170 "4"^^ . _:b357847181 "4"^^ . _:b2578081 . . _:b357847310 . . _:b357847180 "4"^^ . . _:b2578082 . _:b357847183 "4"^^ . _:b357847349 . . _:b2578083 . _:b357847182 "4"^^ . _:b2578092 . _:b357847248 . _:b357847177 "4"^^ . _:b2578093 . _:b2578084 . . _:b357847176 "4"^^ . _:b2578094 . _:b357847330 . _:b357847179 "4"^^ . _:b357847142 . _:b2578095 . _:b357847178 "4"^^ . _:b2578088 . _:b357847189 "3"^^ . _:b2578089 . . _:b357847188 "4"^^ . . _:b2578090 . _:b357847136 . _:b357847191 "3"^^ . _:b2578091 . . _:b357847190 "3"^^ . _:b2578100 . _:b2578085 "Amplification and overexpression of HER2 is seen in about 25\u201330% of breast cancers and occasionally in other cancers (Slamon et al, >>1989<<). The mutational activation of HER2 is also seen in some cancers of the lung (Stephens et al, 2004). In contrast to the other family members, the current evidence suggests that HER4 mediates antiproliferative effects; and consistent with" . . _:b357847185 "4"^^ . _:b2578101 . . _:b357847184 "4"^^ . _:b2578102 . _:b357847197 . _:b357847187 "4"^^ . . _:b2578103 . _:b357847186 "4"^^ . _:b2578096 . . _:b357847182 . _:b357847197 "3"^^ . _:b2578086 . _:b2578097 . . . _:b357847196 "3"^^ . _:b2578098 . _:b357847199 "3"^^ . . . . _:b2578099 . _:b357847198 "3"^^ . _:b2578108 . _:b357847160 . _:b357847193 "3"^^ . _:b2578117 "Characterisation of lung cancers with TKI-sensitive EGFR mutations reveals that PI3K/Akt pathway in these tumours is dependent on HER3 signalling (Engelman et al, >>2005<<). This is analogous to breast cancers with HER2 overexpression, which also depend on HER3 signalling for the activation of PI3K/Akt signalling, discussed above. Tyrosine kinase inhibitor therapy of TKI-sensitive lung cancers inactivates" . _:b2578109 . _:b357847192 "3"^^ . . _:b2578110 . _:b357847195 "3"^^ . _:b2578111 . _:b357847194 "3"^^ . _:b357847335 . _:b2578104 . _:b357847205 "3"^^ . _:b2578105 . _:b357847204 "3"^^ . . . _:b2578106 . _:b357847207 "3"^^ . . _:b2578107 . _:b357847206 "3"^^ . _:b2578116 . _:b357847201 "3"^^ . _:b2578107 "Trastuzumab induces tumour regression in approximately 30\u201335% of patients with HER2-amplified metastatic breast cancer if used as up-front therapy and much less activity if used after other chemotherapies (Tokunaga et al, 2006b). Understanding resistance to trastuzumab has been a challenging problem, and this is largely due to the fact that the mechanisms of response to trastuzumab are not well understood. Trastuzumab binds to the extracellular domain of HER2," . _:b2578117 . _:b357847200 "3"^^ . _:b2578118 . . _:b357847203 "3"^^ . . _:b357847360 . _:b2578119 . _:b357847202 "3"^^ . . _:b357847329 . _:b2578112 . _:b357847213 "3"^^ . . . _:b357847359 . _:b2578113 . _:b357847212 "3"^^ . _:b357847422 . _:b357847319 . _:b2578114 . _:b357847215 "3"^^ . . . . _:b2578115 . _:b357847214 "3"^^ . _:b357847328 . _:b2578124 . _:b357847209 "3"^^ . _:b357847098 . _:b2578125 . _:b357847208 "3"^^ . . _:b357847153 . _:b357847151 . _:b357847211 "3"^^ . _:b357847185 . . . _:b357847210 "3"^^ . . . _:b2578120 . _:b357847221 "3"^^ . _:b2578121 . _:b357847421 . _:b357847220 "3"^^ . _:b2578091 . _:b357847412 . _:b2578122 . _:b357847223 "3"^^ . _:b357847126 . _:b2578123 . _:b357847222 "3"^^ . . _:b357847217 "3"^^ . _:b357847216 "3"^^ . _:b357847219 "3"^^ . _:b2578088 "her2-driven breast cancer" . _:b357847113 . _:b357847218 "3"^^ . . _:b357847229 "3"^^ . _:b357847228 "3"^^ . . _:b357847231 "3"^^ . _:b357847230 "3"^^ . _:b357847234 . _:b357847225 "3"^^ . _:b357847224 "3"^^ . . . _:b357847227 "3"^^ . _:b357847226 "3"^^ . . . _:b357847237 "3"^^ . . _:b357847261 . _:b357847236 "3"^^ . . _:b2578114 "Subsequent studies have identified this subset as patients with cancers driven by mutationally activated EGFR (Lynch et al, >>2004<<). Lung cancers driven by mutated EGFR are highly responsive to TKI therapy (Jackman et al, 2006). The acquisition of TKI resistance in these patients appears to correlate, in part, with the development of kinase domain mutations that" . _:b357847239 "3"^^ . _:b357847253 . _:b357847238 "3"^^ . _:b2578124 "The deletion of PTEN is common in GBMs and correlates with resistance to TKI therapy, and conversely the co-expression of PTEN with EGFRvIII identifies erlotinib-responsive patients (Mellinghoff et al, >>2005<<). The effect of PTEN deletion in this pathway is the constitutive activation of downstream Akt signalling. By removing the negative regulation of phosphoinositide signalling, PTEN deletion uncouples HER3 from the Akt pathway, rendering" . . _:b357847233 "3"^^ . _:b357847108 . _:b357847232 "3"^^ . _:b357847177 . . _:b357847235 "3"^^ . . _:b357847234 "3"^^ . _:b357847245 "2"^^ . _:b357847323 . _:b357847186 . _:b357847244 "2"^^ . _:b357847388 . _:b357847247 "2"^^ . _:b357847246 "2"^^ . _:b357847241 "3"^^ . _:b357847240 "3"^^ . _:b357847243 "2"^^ . . _:b357847242 "3"^^ . _:b357847253 "2"^^ . . _:b357847165 . _:b357847252 "2"^^ . _:b357847390 . _:b2578103 "EGFR is not always expressed in HER2-amplified breast cancers and HER2 is fully capable of transforming EGFR-negative cell models (Chazin et al, >>1992<<)." . _:b357847255 "2"^^ . _:b357847254 "2"^^ . _:b2578098 . _:b357847249 "2"^^ . _:b357847112 . _:b357847248 "2"^^ . _:b357847157 . . . . _:b357847251 "2"^^ . . _:b357847433 . _:b357847202 . _:b357847250 "2"^^ . _:b357847261 "2"^^ . . _:b357847397 . _:b357847260 "2"^^ . _:b357847226 . _:b357847270 . _:b357847263 "2"^^ . _:b357847236 . _:b357847262 "2"^^ . . . _:b357847257 "2"^^ . . . _:b357847256 "2"^^ . _:b2578123 . _:b357847259 "2"^^ . . _:b357847258 "2"^^ . _:b2578096 . _:b357847101 . _:b357847269 "2"^^ . . . _:b357847100 . . _:b357847268 "2"^^ . _:b357847103 . _:b357847271 "2"^^ . _:b357847400 . _:b357847102 . _:b357847270 "2"^^ . _:b357847097 . _:b357847265 "2"^^ . . _:b357847096 . _:b357847264 "2"^^ . . . _:b357847099 . _:b357847267 "2"^^ . _:b2578109 _:b2578110 . _:b2578109 _:b2578111 . _:b357847098 . _:b357847233 . _:b2578106 _:b2578108 . _:b357847266 "2"^^ . _:b357847141 . _:b357847109 . _:b357847277 "2"^^ . _:b2578106 _:b2578107 . _:b357847108 . _:b357847276 "2"^^ . _:b357847111 . _:b2578104 _:b2578105 . _:b357847279 "2"^^ . _:b357847110 . . _:b357847278 "2"^^ . _:b2578081 _:b2578082 . _:b2578081 _:b2578083 . _:b357847105 . _:b2578081 _:b2578084 . _:b2578081 _:b2578085 . _:b357847273 "2"^^ . _:b2578081 _:b2578086 . _:b2578081 _:b2578087 . _:b357847395 . _:b357847104 . _:b357847181 . . _:b357847272 "2"^^ . _:b357847107 . _:b2578122 "Of these tumours, nearly half express the EGFRvIII mutation, which is an in-frame deletion of exons 2\u20137 from the extracellular domain that leads to a constitutively activated receptor (Shinojima et al, >>2003<<). Barriers to effective drug biodistribution in the CNS compartment make this disease more challenging for systemic therapy modalities. But there is evidence from phase I studies that HER family TKIs are active in the treatment of this" . . _:b357847275 "2"^^ . _:b357847106 . _:b357847274 "2"^^ . _:b357847117 . _:b357847285 "2"^^ . _:b357847285 . _:b357847116 . _:b357847102 . _:b357847284 "2"^^ . . _:b357847119 . . _:b357847287 "2"^^ . _:b357847118 . _:b2578093 _:b2578096 . _:b2578093 _:b2578097 . _:b357847286 "2"^^ . _:b2578093 _:b2578098 . _:b2578093 _:b2578099 . _:b357847113 . _:b2578093 _:b2578100 . . . _:b357847281 "2"^^ . _:b2578093 _:b2578101 . _:b2578093 _:b2578102 . _:b357847101 . _:b2578093 _:b2578103 . _:b357847112 . _:b2578088 _:b2578092 . _:b357847280 "2"^^ . _:b357847332 . _:b357847228 . _:b357847115 . _:b357847435 . _:b2578088 _:b2578089 . _:b357847283 "2"^^ . _:b2578088 _:b2578090 . _:b2578088 _:b2578091 . _:b357847114 . _:b357847106 . . _:b357847282 "2"^^ . _:b357847125 . _:b357847293 "2"^^ . . _:b357847124 . _:b357847292 "2"^^ . _:b357847127 . _:b357847295 "2"^^ . _:b2578093 _:b2578094 . _:b2578093 _:b2578095 . _:b357847126 . _:b357847294 "2"^^ . _:b357847311 . _:b357847159 . _:b357847121 . _:b357847289 "2"^^ . _:b357847120 . _:b357847288 "2"^^ . _:b2578121 _:b2578122 . . _:b2578121 _:b2578123 . _:b357847313 . _:b357847123 . _:b2578121 _:b2578124 . _:b2578121 _:b2578125 . _:b357847291 "2"^^ . _:b357847122 . _:b357847107 . _:b357847290 "2"^^ . . _:b357847403 . _:b357847133 . _:b357847301 "2"^^ . _:b357847132 . . _:b357847300 "2"^^ . _:b357847135 . _:b357847303 "2"^^ . _:b357847134 . _:b2578112 _:b2578116 . _:b2578112 _:b2578117 . _:b357847302 "2"^^ . _:b2578112 _:b2578118 . _:b357847199 . _:b357847129 . _:b2578112 _:b2578119 . _:b2578112 _:b2578113 . _:b357847297 "2"^^ . _:b2578112 _:b2578114 . _:b2578112 _:b2578115 . _:b357847128 . _:b357847296 "2"^^ . _:b2578108 "Correlative scientific data from tumour biopsies in some of these studies confirm that TKIs reach their molecular targets and suppress the activity of EGFR and HER2 and downstream MAPK signalling (Spector et al, >>2005<<). Importantly, the inactivation of Akt signalling is not clearly apparent in these studies, suggesting that oncogenic HER2 signalling is not completely suppressed by these therapies. The fact that most HER2-overexpressing breast cancers" . _:b2578085 . _:b2578119 "The development of the EGFR T790M mutation in lung cancers confers drug resistance and is associated with persistent activation of HER3/PI3K/Akt signalling (Engelman et al, >>2006<<). The constitutive activation of HER3 signalling in TKI-resistant lung cancers can also be mediated through the amplification of MET, recently identified in certain TKI-resistant subclones of lung cancer cells (Engelman et al, 2007)" . . _:b357847131 . _:b2578112 _:b2578120 . _:b2578087 . _:b357847299 "2"^^ . . _:b357847130 . _:b357847298 "2"^^ . . . _:b357847141 . _:b357847309 "2"^^ . _:b357847140 . . _:b357847308 "2"^^ . _:b357847143 . _:b357847311 "2"^^ . _:b357847142 . _:b357847188 . _:b357847284 . . _:b357847310 "2"^^ . _:b357847137 . . _:b357847305 "2"^^ . _:b357847136 . _:b357847304 "2"^^ . _:b357847139 . . _:b357847307 "2"^^ . _:b357847138 . _:b2578120 . _:b357847306 "2"^^ . _:b357847149 . _:b357847317 "2"^^ . _:b357847276 . _:b357847148 . . _:b357847316 "2"^^ . _:b357847383 . . _:b357847151 . _:b357847319 "2"^^ . _:b357847150 . . . _:b357847318 "2"^^ . _:b357847222 . _:b357847214 . _:b357847145 . _:b357847269 . _:b357847313 "2"^^ . _:b357847144 . . _:b357847312 "2"^^ . _:b357847147 . _:b357847315 "2"^^ . _:b357847146 . . _:b357847314 "2"^^ . . . _:b357847157 . _:b357847325 "2"^^ . _:b357847156 . _:b357847204 . _:b357847123 . _:b357847324 "2"^^ . _:b357847159 . . _:b357847320 . _:b357847327 "2"^^ . . _:b357847158 . . _:b357847326 "2"^^ . . _:b357847153 . _:b357847121 . _:b357847321 "2"^^ . . . _:b2578121 "targeting her proteins in malignant gliomas" . _:b357847256 . _:b357847152 . _:b357847221 . _:b357847320 "2"^^ . _:b357847155 . _:b357847323 "2"^^ . _:b357847424 . _:b357847154 . _:b357847322 "2"^^ . _:b357847165 . _:b357847333 "2"^^ . _:b357847164 . _:b357847332 "2"^^ . _:b357847140 . _:b357847167 . _:b357847335 "2"^^ . _:b357847166 . _:b357847334 "2"^^ . _:b357847161 . _:b357847329 "2"^^ . _:b357847160 . _:b357847328 "2"^^ . _:b357847163 . _:b357847331 "2"^^ . _:b357847162 . . _:b357847330 "2"^^ . _:b357847219 . _:b357847173 . _:b357847341 "2"^^ . _:b357847172 . _:b357847340 "2"^^ . _:b357847225 . _:b357847175 . _:b357847343 "2"^^ . _:b357847174 . "PMC0" . _:b357847342 "2"^^ . _:b357847439 . _:b357847344 . _:b357847245 . _:b357847169 . _:b357847337 "2"^^ . _:b357847168 . _:b357847336 "2"^^ . _:b357847171 . . _:b357847339 "2"^^ . . . _:b357847170 . _:b357847338 "2"^^ . _:b357847181 . _:b357847349 "2"^^ . _:b357847180 . _:b357847336 . _:b357847348 "2"^^ . _:b357847183 . . _:b357847351 "2"^^ . _:b357847182 . _:b357847350 "2"^^ . . . _:b357847177 . _:b357847324 . _:b357847345 "2"^^ . _:b357847176 . _:b357847344 "2"^^ . . _:b357847179 . _:b357847347 "2"^^ . _:b357847178 . _:b357847346 "2"^^ . . _:b357847189 . _:b357847357 "2"^^ . . . _:b357847188 . _:b357847356 "2"^^ . _:b357847191 . _:b357847359 "2"^^ . . . _:b357847190 . _:b357847358 "2"^^ . _:b357847185 . _:b357847353 "2"^^ . _:b357847184 . _:b357847352 "2"^^ . _:b357847187 . . _:b357847355 "2"^^ . _:b357847186 . . _:b357847354 "2"^^ . _:b357847197 . _:b357847365 "2"^^ . . _:b357847196 . . _:b357847364 "2"^^ . . _:b2578090 "The aetiologic role of HER2 in mammary tumorigenesis has been confirmed by numerous mouse models of constitutively activated HER2 (or its rodent counterpart Neu) (Ursini-Siegel et al, >>2007<<; Moasser, 2007a)." . _:b357847199 . . . _:b357847367 "2"^^ . _:b357847198 . _:b357847366 "2"^^ . _:b357847193 . . . _:b357847361 "2"^^ . . _:b357847192 . _:b357847239 . _:b357847360 "2"^^ . _:b357847195 . _:b357847295 . _:b357847363 "2"^^ . _:b357847194 . _:b357847434 . _:b357847362 "2"^^ . _:b357847205 . _:b357847373 "2"^^ . _:b357847398 . _:b357847204 . _:b357847279 . . _:b2578116 "The acquisition of TKI resistance in these patients appears to correlate, in part, with the development of kinase domain mutations that confer resistance to TKI therapy (Kobayashi et al, >>2005<<). The identification of EGFR mutations in lung cancer has led to an explosion of interest in studying the mechanisms underlying lung cancer pathogenesis, focusing on the role of HER family proteins. An important role for the" . . _:b357847170 . _:b357847372 "2"^^ . _:b357847207 . _:b357847375 "2"^^ . _:b357847206 . . _:b357847374 "2"^^ . _:b357847201 . _:b357847369 "2"^^ . _:b357847200 . _:b357847368 "2"^^ . _:b357847203 . _:b357847364 . _:b357847371 "2"^^ . _:b357847202 . _:b357847370 "2"^^ . _:b357847302 . _:b357847266 . _:b357847213 . _:b357847381 "2"^^ . _:b2578089 "The HER2 gene is amplified and overexpressed in about 25% of breast cancers, conferring a more aggressive biology (Slamon et al, >>1987<<). The aetiologic role of HER2 in mammary tumorigenesis has been confirmed by numerous mouse models of constitutively activated HER2 (or its rodent counterpart Neu) (Ursini-Siegel et al, 2007; Moasser, 2007a). HER2 overexpression is" . _:b357847212 . . . _:b357847380 "2"^^ . _:b357847215 . _:b357847097 . _:b357847383 "2"^^ . . _:b357847214 . _:b357847382 "2"^^ . _:b2578100 "The growth factor activation of PI3K and Akt by HER2 is mediated through the tyrosine phosphorylation of HER3 (Soltoff et al, >>1994<<). Although immunohistochemical reagents are currently unable to directly assay HER3 activity in fixed tissues from clinical studies, the activation of HER3 in the mouse model of HER2-induced tumours is established (Siegel et al, 1999)." . _:b357847209 . _:b357847377 "2"^^ . . _:b357847208 . . _:b357847391 . _:b357847376 "2"^^ . _:b357847211 . _:b357847379 "2"^^ . _:b357847210 . _:b357847378 "2"^^ . _:b357847221 . _:b357847365 . _:b357847389 "2"^^ . _:b357847220 . . . _:b357847115 . _:b357847388 "2"^^ . _:b357847223 . . . _:b357847381 . _:b357847391 "2"^^ . . _:b357847222 . . _:b357847390 "2"^^ . _:b357847217 . _:b357847385 "2"^^ . _:b357847216 . _:b357847384 "2"^^ . _:b357847219 . _:b357847387 "2"^^ . _:b357847218 . _:b357847386 "2"^^ . _:b357847229 . _:b357847382 . _:b357847397 "2"^^ . _:b357847228 . _:b357847396 "2"^^ . _:b357847231 . . _:b357847399 "2"^^ . . _:b357847230 . _:b357847258 . . _:b357847398 "2"^^ . _:b357847225 . _:b357847393 "2"^^ . _:b357847224 . _:b357847404 . _:b357847277 . _:b357847249 . _:b357847392 "2"^^ . _:b357847227 . _:b2578113 . _:b357847395 "2"^^ . _:b357847226 . _:b357847394 "2"^^ . . _:b357847237 . _:b357847405 "2"^^ . _:b357847236 . . . _:b357847404 "2"^^ . _:b2578102 . _:b357847239 . . . . _:b357847407 "2"^^ . _:b357847238 . . . _:b357847406 "2"^^ . _:b2578120 "The constitutive activation of HER3 signalling in TKI-resistant lung cancers can also be mediated through the amplification of MET, recently identified in certain TKI-resistant subclones of lung cancer cells (Engelman et al, >>2007<<) (Figure 1)." . . _:b357847233 . . _:b357847401 "2"^^ . . _:b357847232 . _:b357847379 . _:b357847400 "2"^^ . "10.1038%2Fsj.bjc.6603910" . _:b357847235 . . . . _:b357847403 "2"^^ . _:b357847234 . . . _:b357847402 "2"^^ . _:b357847245 . _:b357847205 . _:b357847413 "2"^^ . . _:b357847244 . . _:b357847412 "2"^^ . _:b357847247 . _:b357847259 . _:b357847415 "2"^^ . _:b357847246 . _:b2578119 . . . _:b357847414 "2"^^ . . _:b357847174 . _:b357847241 . . . _:b357847409 "2"^^ . . . . _:b357847240 . _:b357847252 . _:b357847408 "2"^^ . _:b357847243 . . _:b357847411 "2"^^ . . _:b357847281 . . _:b357847242 . _:b357847410 "2"^^ . _:b357847253 . . _:b357847257 . _:b357847421 "2"^^ . _:b357847252 . . _:b357847420 "2"^^ . _:b357847191 . _:b357847255 . _:b357847120 . _:b357847305 . _:b357847423 "2"^^ . . _:b357847254 . . _:b357847422 "2"^^ . _:b2578112 "targeting her proteins in nsclc" . . _:b357847249 . _:b357847309 . _:b357847417 "2"^^ . _:b357847248 . _:b357847416 "2"^^ . _:b357847251 . _:b357847419 "2"^^ . _:b357847250 . _:b357847406 . _:b357847418 "2"^^ . _:b357847218 . _:b357847261 . _:b2578115 "Lung cancers driven by mutated EGFR are highly responsive to TKI therapy (Jackman et al, >>2006<<). The acquisition of TKI resistance in these patients appears to correlate, in part, with the development of kinase domain mutations that confer resistance to TKI therapy (Kobayashi et al, 2005). The identification of EGFR mutations in" . . _:b357847429 "2"^^ . _:b357847260 . _:b357847195 . _:b2578102 "Akt activity, however, can be assayed in clinical samples, and the clinical data indeed shows frequent activation of Akt in HER2-expressing tumours (Tokunaga et al, 2006a). The role of Akt as a critical proliferative and antiapoptotic signal as well as its contributions to cell invasiveness and metastasis are beyond the scope of this review. However, a plethora of evidence confirm that Akt regulates vital" . _:b357847428 "2"^^ . _:b357847263 . _:b357847431 "2"^^ . _:b357847262 . . _:b357847430 "2"^^ . _:b357847257 . _:b2578081 "her family" . _:b357847146 . . _:b357847425 "2"^^ . . _:b357847256 . _:b357847128 . _:b2578122 . _:b357847190 . _:b357847424 "2"^^ . . _:b357847259 . . _:b357847427 "2"^^ . _:b357847289 . _:b357847258 . _:b357847378 . _:b357847426 "2"^^ . _:b357847269 . _:b357847437 "2"^^ . _:b357847316 . _:b357847268 . . _:b357847436 "2"^^ . _:b2578082 . _:b357847271 . _:b357847282 . _:b357847439 "2"^^ . _:b357847270 . _:b357847438 "2"^^ . _:b357847265 . _:b357847428 . _:b357847433 "2"^^ . _:b357847375 . . _:b357847264 . _:b357847432 "2"^^ . _:b357847267 . _:b357847435 "2"^^ . _:b357847266 . _:b357847434 "2"^^ . _:b357847277 . _:b357847275 . _:b357847235 . _:b357847276 . _:b357847371 . _:b357847279 . _:b357847386 . _:b357847427 . _:b357847223 . _:b357847278 . _:b357847322 . _:b2578105 "a mechanistic basis for this activity is difficult to explain, since EGFR activation is not commonly seen in colon cancers, and the clinical activities of EGFR-targeted therapies shows no correlation with EGFR expression (Chung et al, >>2005<<)." . _:b357847099 . _:b357847273 . _:b357847139 . _:b357847272 . . . _:b357847440 "2"^^ . _:b357847275 . . . _:b357847274 . _:b357847334 . _:b357847285 . . _:b357847284 . _:b357847103 . _:b357847287 . . _:b357847425 . _:b357847286 . . . . _:b357847281 . _:b357847280 . _:b2578123 "But there is evidence from phase I studies that HER family TKIs are active in the treatment of this disease (Prados et al, >>2006<<). Molecular determinants of treatment response have been studied in patients with GBM. The deletion of PTEN is common in GBMs and correlates with resistance to TKI therapy, and conversely the co-expression of PTEN with EGFRvIII identifies" . _:b357847283 .