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Subject Item: n2:26041671
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n3:pmcid: PMC0
bibo:doi: 10.1186%2Fs12943-015-0392-3
n7:contains: _:vb41359961 _:vb41359985 _:vb41359991 _:vb41359979 _:vb41360013

Subject Item: _:vb41359961
rdf:type: n7:Section
dc:title: results
n7:contains: _:vb41359962 _:vb41359963 _:vb41359964 _:vb41359965 _:vb41359966 _:vb41359967 _:vb41359968 _:vb41359969 _:vb41359970 _:vb41359971 _:vb41359972 _:vb41359973 _:vb41359974 _:vb41359975 _:vb41359976 _:vb41359977 _:vb41359978

Subject Item: _:vb41359962
rdf:type: n3:Context
rdf:value: previously demonstrated that pIGF-1R/IR levels are significantly higher in premalignant human lung epithelial tissue sample than in normal or reactive bronchial specimens and significantly correlated with the levels of IGF1 and IGF2 [>>18<<]. We have also shown that lung tumors can be formed by the lung-specific overexpression of IGF1 [18].
n3:mentions: n2:19738076

Subject Item: _:vb41359963
rdf:type: n3:Context
rdf:value: We have also shown that lung tumors can be formed by the lung-specific overexpression of IGF1 [>>18<<]. These results indicate the importance of tissue-derived IGF expression in the activation of the IGF-1R pathway at an early stage of lung carcinogenesis. We recently reported substantial levels of phosphorylated IGF-1R at tyrosine 1131
n3:mentions: n2:19738076

Subject Item: _:vb41359964
rdf:type: n3:Context
rdf:value: reported substantial levels of phosphorylated IGF-1R at tyrosine 1131 (tyrosine 1158 for IR) or tyrosines 1135 and 1136 (tyrosines 1162 and 1163 for IR) (pIGF-1R, hereafter) and IGF expression in tissue specimens from NSCLC patients [>>15<<, 16]. In the current study, we investigated whether the ligand-dependent activation of the IGF-1R occurs in NSCLC by analyzing previously studied tissue specimens from NSCLC patients.
n3:mentions: n2:21952750

Subject Item: _:vb41359965
rdf:type: n3:Context
rdf:value: substantial levels of phosphorylated IGF-1R at tyrosine 1131 (tyrosine 1158 for IR) or tyrosines 1135 and 1136 (tyrosines 1162 and 1163 for IR) (pIGF-1R, hereafter) and IGF expression in tissue specimens from NSCLC patients [15, >>16<<]. In the current study, we investigated whether the ligand-dependent activation of the IGF-1R occurs in NSCLC by analyzing previously studied tissue specimens from NSCLC patients.
n3:mentions: n2:22359227

Subject Item: _:vb41359966
rdf:type: n3:Context
rdf:value: Based on previous findings suggesting that Src can activate IGF-1R in a ligand-independent manner [>>19<<], we examined the relationship between IGF-1R and Src in NSCLC.
n3:mentions: n2:7525552

Subject Item: _:vb41359967
rdf:type: n3:Context
rdf:value: We also observed high levels of membrane-associated receptors including EGFR, integrins β1 and β3, and/or c-Met, all of which are involved in Src activation [>>14<<], in most of the NSCLC cell lines.
n3:mentions: n2:22153719

Subject Item: _:vb41359968
rdf:type: n3:Context
rdf:value: Transfection with the constitutively active Src phosphorylated IGF-1R, EGFR (Y1068 and Y845), Src, and FAK (Y576, a Src-specific phosphorylation site [>>21<<]), and Akt (S473) but not FAK (Y397, an integrin signaling-induced autophosphorylation site [22]) or ERK1/2 in H226Br and H226B cells (Fig.
n3:mentions: n2:15735019

Subject Item: _:vb41359969
rdf:type: n3:Context
rdf:value: with the constitutively active Src phosphorylated IGF-1R, EGFR (Y1068 and Y845), Src, and FAK (Y576, a Src-specific phosphorylation site [21]), and Akt (S473) but not FAK (Y397, an integrin signaling-induced autophosphorylation site [>>22<<]) or ERK1/2 in H226Br and H226B cells (Fig. 2a). We next assessed whether Src activation via various signaling pathways would affect IGF-1R phosphorylation.
n3:mentions: n2:12960434

Subject Item: _:vb41359970
rdf:type: n3:Context
rdf:value: EGF stimulation increased EGFR, Akt, Src, and IGF-1R phosphorylation in A549 and H460 cells but not in H522, a low EGFR-expressing cell line [>>23<<] (Fig. 2b). This EGF-induced IGF-1R phosphorylation was suppressed by treatment with the clinically available small molecular Src inhibitor dasatinib [24] (Fig. 2c), by transfection with an siRNA against Src (Fig. 2d), and by treatment
n3:mentions: n2:15078990

Subject Item: _:vb41359971
rdf:type: n3:Context
rdf:value: This EGF-induced IGF-1R phosphorylation was suppressed by treatment with the clinically available small molecular Src inhibitor dasatinib [>>24<<] (Fig. 2c), by transfection with an siRNA against Src (Fig. 2d), and by treatment with the EGFR TKI erlotinib, but the IGF-1R TKI linsitinib exhibited relatively minimal effects on the suppression of EGF-induced IGF-1R phosphorylation
n3:mentions: n2:21226671

Subject Item: _:vb41359972
rdf:type: n3:Context
rdf:value: Previous reports suggested that Src can directly phosphorylate IGF-1R at the sites of ligand-induced autophosphorylation [>>12<<, 13]. Consistent with this finding, in vitro kinase assays showed the ability of Src, derived from A549 cells or recombinant protein (rSrc), to phosphorylate recombinant IGF-1R protein (GST-IGF-1R) (Fig.
n3:mentions: n2:15170449

Subject Item: _:vb41359973
rdf:type: n3:Context
rdf:value: Previous reports suggested that Src can directly phosphorylate IGF-1R at the sites of ligand-induced autophosphorylation [12, >>13<<]. Consistent with this finding, in vitro kinase assays showed the ability of Src, derived from A549 cells or recombinant protein (rSrc), to phosphorylate recombinant IGF-1R protein (GST-IGF-1R) (Fig.
n3:mentions: n2:8940173

Subject Item: _:vb41359974
rdf:type: n3:Context
rdf:value: In contrast to the wild-type receptor, this mutant was unresponsive to IGF-stimulated IGF-1R tyrosine phosphorylation [>>25<<], confirming the importance of the site for receptor activity.
n3:mentions: n2:16793764

Subject Item: _:vb41359975
rdf:type: n3:Context
rdf:value: Combined treatment with another SFK inhibitor PP2 [>>26<<] also decreased linsitinib-induced IGF-1R, Src, and Akt phoshsphorylation in H460 cells (Additional file 13:
n3:mentions: n2:8557675

Subject Item: _:vb41359976
rdf:type: n3:Context
rdf:value: We then assessed the sensitivity of NSCLC cells to linsitinib in medium containing low (1 %) or high (10 %) fetal bovine serum (FBS), which contains various ligands for the membrane-associated receptors [>>27<<]. Linsitinib treatment decreased viability (Additional file 15: Figure S14A) and colony forming ability (Additional file 15:
n3:mentions: n2:17022666

Subject Item: _:vb41359977
rdf:type: n3:Context
rdf:value: file 18: Figure S17B) and anchorage-independent colony formation (Additional file 18: Figure S17C) were also observed in both high-pSrc-expressing and low-pSrc-expressing NSCLC cells when another pharmacologic SFK inhibitor, PP2 [>>26<<], was combined with linsitinib. Notably, co-targeting Src and IGF-1R effectively suppressed the colony formation of EGFR TKI-resistant NSCLC cells (H1975, PC-9/GR and PC-9/ER) [28] (Additional file 18:
n3:mentions: n2:8557675

Subject Item: _:vb41359978
rdf:type: n3:Context
rdf:value: Notably, co-targeting Src and IGF-1R effectively suppressed the colony formation of EGFR TKI-resistant NSCLC cells (H1975, PC-9/GR and PC-9/ER) [>>28<<] (Additional file 18:
n3:mentions: n2:18227510

Subject Item: _:vb41359979
rdf:type: n7:Section
dc:title: conclusions
n7:contains: _:vb41359980 _:vb41359981 _:vb41359982 _:vb41359983 _:vb41359984

Subject Item: _:vb41359980
rdf:type: n3:Context
rdf:value: Because the clinical development of TKIs of IGF-1R and Src is ongoing [>>45<<, 46], our findings directly impact the current clinical management of patients with NSCLC.
n3:mentions: n2:19663769

Subject Item: _:vb41359981
rdf:type: n3:Context
rdf:value: Because the clinical development of TKIs of IGF-1R and Src is ongoing [45, >>46<<], our findings directly impact the current clinical management of patients with NSCLC.
n3:mentions: n2:19787002

Subject Item: _:vb41359982
rdf:type: n3:Context
rdf:value: It is noteworthy that a phase I trial of solid tumors treated with XL228 (a small molecule inhibitor targeting Src family kinases, IGF-1R, Aurora A, and Bcr-Abl in the low nanomolar range [>>47<<]) has shown promising preliminary clinical results in melanoma and solid tumors including NSLCLC [48].
n3:mentions: n2:20557276

Subject Item: _:vb41359983
rdf:type: n3:Context
rdf:value: Considering the extensive toxicities of Src inhibitors and IGF-1R TKIs [>>49<<, 50], further studies are warranted to evaluate the efficacy of co-targeting IGF-1R and Src in additional preclinical and clinical settings.
n3:mentions: n2:17259557

Subject Item: _:vb41359984
rdf:type: n3:Context
rdf:value: Considering the extensive toxicities of Src inhibitors and IGF-1R TKIs [49, >>50<<], further studies are warranted to evaluate the efficacy of co-targeting IGF-1R and Src in additional preclinical and clinical settings.
n3:mentions: n2:19689244

Subject Item: _:vb41359985
rdf:type: n7:Section
dc:title: methods
n7:contains: _:vb41359986 _:vb41359987 _:vb41359988 _:vb41359989 _:vb41359990

Subject Item: _:vb41359986
rdf:type: n3:Context
rdf:value: The pBabe-Puro EGFR WT plasmid was purchased from Addgene (catalog # 11011, Cambridge, MA, USA) [>>51<<]. The mutant Src (Y527F) expression vector was kindly provided by Dr. Faye M. Johnson (MD Anderson Cancer Center, Houston, TX, USA).
n3:mentions: n2:16187797

Subject Item: _:vb41359987
rdf:type: n3:Context
rdf:value: Total RNA isolation and RT-PCR were performed as described previously [>>5<<] using the following primer sequences:
n3:mentions: n2:17047074

Subject Item: _:vb41359988
rdf:type: n3:Context
rdf:value: Immunohistochemical analyses to detect PCNA, cleaved caspase-3, pIGF-1R, and pSrc expression in the xenograft and PDX tumors were performed as described previously [>>52<<]. In brief, formalin-fixed and paraffin-embedded tissue sections (4 μm) were deparaffinized, dehydrated, and treated with methanol containing 3 % hydrogen peroxide.
n3:mentions: n2:24942865

Subject Item: _:vb41359989
rdf:type: n3:Context
rdf:value: The detailed procedures for immunohistochemical analysis and scoring of tissue microarray were described in our previous report [>>15<<].
n3:mentions: n2:21952750

Subject Item: _:vb41359990
rdf:type: n3:Context
rdf:value: The quantitative analysis of blots using densitometry was performed with Image J software (National Institute of Health, Bethesda, MD, USA) [>>53<<]. The statistical significance of the data obtained from the in vitro experiments was analyzed using two-sided Student’s t-tests. The statistical significance of data obtained from the in vivo experiments was analyzed via one-way or
n3:mentions: n2:22930834

Subject Item: _:vb41359991
rdf:type: n7:Section
dc:title: discussion
n7:contains: _:vb41359992 _:vb41359993 _:vb41359994 _:vb41359995 _:vb41359996 _:vb41359997 _:vb41359998 _:vb41359999 _:vb41360008 _:vb41360009 _:vb41360010 _:vb41360011 _:vb41360012 _:vb41360000 _:vb41360001 _:vb41360002 _:vb41360003 _:vb41360004 _:vb41360005 _:vb41360006 _:vb41360007

Subject Item: _:vb41359992
rdf:type: n3:Context
rdf:value: These results, together with previous reports and our current findings showing the simultaneous over-expression/activation of multiple membrane-associated receptors in NSCLCs [>>29<<–31], suggest that combination regimens of molecularly targeted agents against IGF-1R and Src have a great potential for anticancer therapies.
n3:mentions: n2:21447712 n2:19153117 n2:20924128

Subject Item: _:vb41359993
rdf:type: n3:Context
rdf:value: a major role in mediating the activation of prosurvival pathways and contributes to resistance to various anticancer therapies, including chemotherapies, radiation therapy, and molecular targeted therapies, in multiple cancer types [>>5<<–7, 11, 32]. These findings indicate that IGF-1R-targeted therapies represent a promising single-agent or combination regimen.
n3:mentions: n2:17047074 n2:21907495 n2:18670298

Subject Item: _:vb41359994
rdf:type: n3:Context
rdf:value: major role in mediating the activation of prosurvival pathways and contributes to resistance to various anticancer therapies, including chemotherapies, radiation therapy, and molecular targeted therapies, in multiple cancer types [5–7, >>11<<, 32]. These findings indicate that IGF-1R-targeted therapies represent a promising single-agent or combination regimen.
n3:mentions: n2:20975071

Subject Item: _:vb41359995
rdf:type: n3:Context
rdf:value: role in mediating the activation of prosurvival pathways and contributes to resistance to various anticancer therapies, including chemotherapies, radiation therapy, and molecular targeted therapies, in multiple cancer types [5–7, 11, >>32<<]. These findings indicate that IGF-1R-targeted therapies represent a promising single-agent or combination regimen.
n3:mentions: n2:17473213

Subject Item: _:vb41359996
rdf:type: n3:Context
rdf:value: laboratory has shown that the inactivation of IGF-1R by the IGF-1R mAb resulted in enhanced signaling through IGF-dependent integrin/Src signaling and the Akt/mTOR-mediated protein synthesis of EGFR and Akt, leading to drug resistance [>>33<<, 34]. IR has also been suggested to mediate intrinsic and/or acquired resistance to IGF-1R mAbs [30, 35].
n3:mentions: n2:21980128

Subject Item: _:vb41359997
rdf:type: n3:Context
rdf:value: has shown that the inactivation of IGF-1R by the IGF-1R mAb resulted in enhanced signaling through IGF-dependent integrin/Src signaling and the Akt/mTOR-mediated protein synthesis of EGFR and Akt, leading to drug resistance [33, >>34<<]. IR has also been suggested to mediate intrinsic and/or acquired resistance to IGF-1R mAbs [30, 35].
n3:mentions: n2:24092920

Subject Item: _:vb41359998
rdf:type: n3:Context
rdf:value: IR has also been suggested to mediate intrinsic and/or acquired resistance to IGF-1R mAbs [>>30<<, 35]. In this regard, dual IGF-1R/IR TKI regimens may be more effective in blocking the IGF-1R pathway in patients with NSCLC. However, the dual IGF-1R/IR TKI linsitinib has shown moderate efficacy and/or severe toxicity in multiple
n3:mentions: n2:20924128

Subject Item: _:vb41359999
rdf:type: n3:Context
rdf:value: IR has also been suggested to mediate intrinsic and/or acquired resistance to IGF-1R mAbs [30, >>35<<]. In this regard, dual IGF-1R/IR TKI regimens may be more effective in blocking the IGF-1R pathway in patients with NSCLC. However, the dual IGF-1R/IR TKI linsitinib has shown moderate efficacy and/or severe toxicity in multiple
n3:mentions: n2:20457905

Subject Item: _:vb41360000
rdf:type: n3:Context
rdf:value: However, the dual IGF-1R/IR TKI linsitinib has shown moderate efficacy and/or severe toxicity in multiple preclinical and clinical studies for various types of cancer3 [>>36<<, 37]. Furthermore, the major components of the IGF-1R pathway, such as pIGF-1R, pAkt, pERK, pIRS, and pS6K, could not predict response to linsitinib [38]. Therefore, identifying and targeting the mechanism of resistance against the IGF-1R
n3:mentions: n2:22161861

Subject Item: _:vb41360001
rdf:type: n3:Context
rdf:value: However, the dual IGF-1R/IR TKI linsitinib has shown moderate efficacy and/or severe toxicity in multiple preclinical and clinical studies for various types of cancer3 [36, >>37<<]. Furthermore, the major components of the IGF-1R pathway, such as pIGF-1R, pAkt, pERK, pIRS, and pS6K, could not predict response to linsitinib [38]. Therefore, identifying and targeting the mechanism of resistance against the IGF-1R
n3:mentions: n2:23515613

Subject Item: _:vb41360002
rdf:type: n3:Context
rdf:value: Furthermore, the major components of the IGF-1R pathway, such as pIGF-1R, pAkt, pERK, pIRS, and pS6K, could not predict response to linsitinib [>>38<<]. Therefore, identifying and targeting the mechanism of resistance against the IGF-1R TKIs would be effective and clinically practical in controlling prosurvival pathways.
n3:mentions: n2:20530704

Subject Item: _:vb41360003
rdf:type: n3:Context
rdf:value: De novo and acquired resistance to inhibitors of RTK have been suggested to occur due to the mutation, amplification, and increased/decreased expression of signaling molecules involved in multiple counter-regulatory pathways [>>39<<]. However, unlike EGFR, neither activating mutations nor gene amplifications of IGF-1R are common [40].
n3:mentions: n2:20008847

Subject Item: _:vb41360004
rdf:type: n3:Context
rdf:value: However, unlike EGFR, neither activating mutations nor gene amplifications of IGF-1R are common [>>40<<]. We have demonstrated that the activation of the IGF-1R pathway through the increased expression of tissue-derived IGFs and the loss of IGFBP-3 is an early event in lung carcinogenesis [18, 41]. However, an analysis of previously studied
n3:mentions: n2:24212944

Subject Item: _:vb41360005
rdf:type: n3:Context
rdf:value: We have demonstrated that the activation of the IGF-1R pathway through the increased expression of tissue-derived IGFs and the loss of IGFBP-3 is an early event in lung carcinogenesis [>>18<<, 41]. However, an analysis of previously studied tissue specimens from NSCLC patients and a panel of NSCLC cell lines revealed no correlation between the expression levels of pIGF-1R and IGFs. The previous reports, including; 1) the
n3:mentions: n2:19738076

Subject Item: _:vb41360006
rdf:type: n3:Context
rdf:value: We have demonstrated that the activation of the IGF-1R pathway through the increased expression of tissue-derived IGFs and the loss of IGFBP-3 is an early event in lung carcinogenesis [18, >>41<<]. However, an analysis of previously studied tissue specimens from NSCLC patients and a panel of NSCLC cell lines revealed no correlation between the expression levels of pIGF-1R and IGFs. The previous reports, including; 1) the mutation
n3:mentions: n2:12473592

Subject Item: _:vb41360007
rdf:type: n3:Context
rdf:value: The previous reports, including; 1) the mutation and/or overexpression of various molecules involved in Src activation, such as EGFR, KRas, and HER2 [>>16<<, 29], has been implicated in the mechanism of resistance to IGF-1R TKIs [16]; and 2) the aberrant overexpression and activation of IGF-1R and Src in many NSCLCs [42], and our current results, indicating; 1) a strong positive correlation
n3:mentions: n2:22359227

Subject Item: _:vb41360008
rdf:type: n3:Context
rdf:value: The previous reports, including; 1) the mutation and/or overexpression of various molecules involved in Src activation, such as EGFR, KRas, and HER2 [16, >>29<<], has been implicated in the mechanism of resistance to IGF-1R TKIs [16]; and 2) the aberrant overexpression and activation of IGF-1R and Src in many NSCLCs [42], and our current results, indicating; 1) a strong positive correlation
n3:mentions: n2:21447712

Subject Item: _:vb41360009
rdf:type: n3:Context
rdf:value: The previous reports, including; 1) the mutation and/or overexpression of various molecules involved in Src activation, such as EGFR, KRas, and HER2 [16, 29], has been implicated in the mechanism of resistance to IGF-1R TKIs [>>16<<]; and 2) the aberrant overexpression and activation of IGF-1R and Src in many NSCLCs [42], and our current results, indicating; 1) a strong positive correlation between pSrc and pIGF-1R in a large TMA of NSCLC tissues and in the majority
n3:mentions: n2:22359227

Subject Item: _:vb41360010
rdf:type: n3:Context
rdf:value: molecules involved in Src activation, such as EGFR, KRas, and HER2 [16, 29], has been implicated in the mechanism of resistance to IGF-1R TKIs [16]; and 2) the aberrant overexpression and activation of IGF-1R and Src in many NSCLCs [>>42<<], and our current results, indicating; 1) a strong positive correlation between pSrc and pIGF-1R in a large TMA of NSCLC tissues and in the majority of NSCLC cell lines; 2) the suppression of EGFR- or integrinβ3 -mediated activation of
n3:mentions: n2:18388349

Subject Item: _:vb41360011
rdf:type: n3:Context
rdf:value: Recent studies suggest that second- and third-generation EGFR inhibitors are more potent than gefitinib or erlotinib (at least in pre-clinical models) against the drug-resistant mutation [>>43<<]. In addition, several combination strategies, including the combination of EGFR TKIs with inhibitors of downstream EGFR targets, such as PI3K or STAT5, have been tested in preclinical models of EGFR-mutant NSCLCs [44]. Although these
n3:mentions: n2:15897464

Subject Item: _:vb41360012
rdf:type: n3:Context
rdf:value: In addition, several combination strategies, including the combination of EGFR TKIs with inhibitors of downstream EGFR targets, such as PI3K or STAT5, have been tested in preclinical models of EGFR-mutant NSCLCs [>>44<<]. Although these strategies are promising, their clinical efficacy remains to be evaluated. Hence, there is a need for alternative strategies to address the problem of resistance to EGFR TKIs. In this regard, our current findings suggest
n3:mentions: n2:18166498

Subject Item: _:vb41360013
rdf:type: n7:Section
dc:title: background
n7:contains: _:vb41360016 _:vb41360017 _:vb41360018 _:vb41360019 _:vb41360020 _:vb41360021 _:vb41360022 _:vb41360023 _:vb41360024 _:vb41360025 _:vb41360026 _:vb41360014 _:vb41360015

Subject Item: _:vb41360014
rdf:type: n3:Context
rdf:value: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide [>>1<<], and the 5-year survival rate for patients with advanced NSCLC remains less than 20 % [2].
n3:mentions: n2:21296855

Subject Item: _:vb41360015
rdf:type: n3:Context
rdf:value: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide [1], and the 5-year survival rate for patients with advanced NSCLC remains less than 20 % [>>2<<]. Although a small subset of patients with specific genetic and epigenetic abnormalities has shown clinical response to specific targeted therapies [3], most patients with NSCLCs are insensitive to chemotherapy and radiation1.
n3:mentions: n2:23335087

Subject Item: _:vb41360016
rdf:type: n3:Context
rdf:value: Although a small subset of patients with specific genetic and epigenetic abnormalities has shown clinical response to specific targeted therapies [>>3<<], most patients with NSCLCs are insensitive to chemotherapy and radiation1.
n3:mentions: n2:19914732

Subject Item: _:vb41360017
rdf:type: n3:Context
rdf:value: Moreover, acquired resistance to the therapies eventually emerges in the initially sensitive patients after continuous treatment [>>4<<]. As activation of the survival potential seem to provide cancer cells resistance to anticancer therapies, it is likely that effective anticancer therapies must occur in parallel with blockade of key survival pathways.
n3:mentions: n2:24981256

Subject Item: _:vb41360018
rdf:type: n3:Context
rdf:value: The insulin-like growth factor receptor (IGF-1R) signaling pathway plays a critical role in cancer cell survival, causing resistance to numerous anticancer drugs [>>5<<–7]. Therefore, effective regimens to inactivate the IGF-1R pathway may sensitize cancer cells to anticancer therapies and provide clinical benefits to cancer patients.
n3:mentions: n2:21907495 n2:17047074 n2:18670298

Subject Item: _:vb41360019
rdf:type: n3:Context
rdf:value: However, patients who show a promising initial response to anti-IGF-1R monoclonal antibodies (mAbs) appear to rapidly acquire resistance to these mAbs [>>8<<–10]. Similarly, therapeutic efficacy of IGF-1R TKIs has been modest in a variety of human cancers, including NSCLC2 thus, there is an urgent need to understand the signaling pathways that confer inherent and/or acquired resistance to
n3:mentions: n2:22234739 n2:20713879 n2:22025157

Subject Item: _:vb41360020
rdf:type: n3:Context
rdf:value: The canonical activation of IGF-1R results from the binding of ligands (IGF1 and IGF2) to IGF-IR, insulin receptor (IR) (with a lower affinity than insulin), and hybrid receptors of IGF-1R/IR [>>6<<, 11], leading to the autophosphorylation of tyrosine residues 1131, 1135, and 1136 in the activation loop of the IGF-1R β-chain (the corresponding residues in the human IR are 1158, 1162, and 1163, respectively).
n3:mentions: n2:18670298

Subject Item: _:vb41360021
rdf:type: n3:Context
rdf:value: The canonical activation of IGF-1R results from the binding of ligands (IGF1 and IGF2) to IGF-IR, insulin receptor (IR) (with a lower affinity than insulin), and hybrid receptors of IGF-1R/IR [6, >>11<<], leading to the autophosphorylation of tyrosine residues 1131, 1135, and 1136 in the activation loop of the IGF-1R β-chain (the corresponding residues in the human IR are 1158, 1162, and 1163, respectively).
n3:mentions: n2:20975071

Subject Item: _:vb41360022
rdf:type: n3:Context
rdf:value: Previous reports have suggested that Src, a non-receptor protein tyrosine kinase, can directly phosphorylate IGF-1R [>>12<<, 13]. Src also plays an important role in cancer cell survival and resistance to targeted anticancer therapies by acting as a common signaling facilitator that is activated by a myriad of redundant signaling pathways [12, 14]. The
n3:mentions: n2:15170449

Subject Item: _:vb41360023
rdf:type: n3:Context
rdf:value: Previous reports have suggested that Src, a non-receptor protein tyrosine kinase, can directly phosphorylate IGF-1R [12, >>13<<]. Src also plays an important role in cancer cell survival and resistance to targeted anticancer therapies by acting as a common signaling facilitator that is activated by a myriad of redundant signaling pathways [12, 14]. The elevated
n3:mentions: n2:8940173

Subject Item: _:vb41360024
rdf:type: n3:Context
rdf:value: Src also plays an important role in cancer cell survival and resistance to targeted anticancer therapies by acting as a common signaling facilitator that is activated by a myriad of redundant signaling pathways [>>12<<, 14]. The elevated expression and/or activation of Src and multiple membrane-associated receptors, such as IGF-1R, IR integrins, HER2/neu, and EGFR (all of which trigger Src activation), have been reported in NSCLCs [14–17]. Hence, it is
n3:mentions: n2:15170449

Subject Item: _:vb41360025
rdf:type: n3:Context
rdf:value: Src also plays an important role in cancer cell survival and resistance to targeted anticancer therapies by acting as a common signaling facilitator that is activated by a myriad of redundant signaling pathways [12, >>14<<]. The elevated expression and/or activation of Src and multiple membrane-associated receptors, such as IGF-1R, IR integrins, HER2/neu, and EGFR (all of which trigger Src activation), have been reported in NSCLCs [14–17]. Hence, it is
n3:mentions: n2:22153719

Subject Item: _:vb41360026
rdf:type: n3:Context
rdf:value: The elevated expression and/or activation of Src and multiple membrane-associated receptors, such as IGF-1R, IR integrins, HER2/neu, and EGFR (all of which trigger Src activation), have been reported in NSCLCs [>>14<<–17]. Hence, it is likely that Src acts as a downstream node that links signalings among several collateral membrane associated receptors.
n3:mentions: n2:22359227 n2:21952750 n2:22153719 n2:12826049

Subject Item: _:vb581303784
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 6
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Subject Item: _:vb581303785
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 4
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Subject Item: _:vb581303786
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 4
n3:hasRelevantPaperId: n2:19318572

Subject Item: _:vb581303787
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:17047074

Subject Item: _:vb581303788
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:18670298

Subject Item: _:vb581303789
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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Subject Item: _:vb581303790
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:21156289

Subject Item: _:vb581303791
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:15170449

Subject Item: _:vb581303792
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:24873489

Subject Item: _:vb581303793
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
n3:hasRelevantPaperId: n2:25925378

Subject Item: _:vb581303794
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:11900220

Subject Item: _:vb581303795
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:24932685

Subject Item: _:vb581303796
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:26465273

Subject Item: _:vb581303797
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:22310287

Subject Item: _:vb581303798
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:21425998

Subject Item: _:vb581303799
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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Subject Item: _:vb581303800
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:20404007

Subject Item: _:vb581303801
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:23619944

Subject Item: _:vb581303802
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:19581523

Subject Item: _:vb581303803
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:26358373

Subject Item: _:vb581303804
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:21907495

Subject Item: _:vb581303805
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:25984556

Subject Item: _:vb581303806
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:8557675

Subject Item: _:vb581303807
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:15229476

Subject Item: _:vb581303808
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:22761272

Subject Item: _:vb581303809
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:25303978

Subject Item: _:vb581303810
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:21300544

Subject Item: _:vb581303811
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:19610618

Subject Item: _:vb581303812
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:22359227

Subject Item: _:vb581303813
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:24316974

Subject Item: _:vb581303814
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:27115835

Subject Item: _:vb581303815
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:15901923

Subject Item: _:vb581303816
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:22500798

Subject Item: _:vb581303817
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:24763074

Subject Item: _:vb581303818
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:8940173

Subject Item: _:vb581303819
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:18566589

Subject Item: _:vb581303820
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:24565571