Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC

Terai, Hideki; Soejima, Kenzo; Yasuda, Hiroyuki; Nakayama, Sohei; Hamamoto, Junko; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Ikemura, Shinnosuke; Sato, Takashi; Yoda, Satoshi; Satomi, Ryosuke; Naoki, Katsuhiko; Betsuyaku, Tomoko

doi:10.1158/1541-7786.mcr-12-0652

Cited by 175 publications

(167 citation statements)

References 30 publications

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“…Similarly, we noted that fibroblast growth factor receptor (FGFR) family kinase genes FGFR1 and FGFR2, though not previously recognized as sufficient for EGFR bypass, nonetheless align with previous work describing up-regulation of FGFR1 as well as the ligand FGF2 in gefitinib-resistant NSCLC models, with concomitant dependency on the FGFR pathway (33,34), and with other studies implicating FGF ligands in TKI resistance (15,35).…”

Section: Discussionsupporting

confidence: 88%

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Sharifnia

Rusu

Piccioni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFRdependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFRindependent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. epidermal growth factor receptor | non-small cell lung cancer | ORF

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Section: Discussionsupporting

confidence: 88%

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Sharifnia

Rusu

Piccioni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Co-inhibition with lapatinib sensitized these cells to FGFR inhibitor. Previous studies have also shown cross talk between FGFR and ERBB pathway in multiple tumor types [36][37][38] . In lung cancer, activation of FGFR pathway is a cause of acquired resistance to EGFR 21 inhibitors in EGFR mutant cancer cell lines 36 .…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have also shown cross talk between FGFR and ERBB pathway in multiple tumor types [36][37][38] . In lung cancer, activation of FGFR pathway is a cause of acquired resistance to EGFR 21 inhibitors in EGFR mutant cancer cell lines 36 . Also, a switch from dependency on In conclusion, we have demonstrated that high FGFR1 protein expression is surprisingly absent in a significant number of FGFR1-amplified lung cancers, and these cancers are uniformly resistant to FGFR inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression

et al. 2015

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Targeted therapies are effective in subsets of lung cancers with EGFR mutations and ALK translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in roughly 20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarkerdirected FGFR inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK translocated lung cancers treated with EGFR inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression, and protein expression of FGFR1 were assessed in cell lines, tumor specimens, and data from The Cancer Genome Atlas (TCGA). The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors.

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“…Both EGFR and FGFR have been reported to be overexpressed and likely contributors in ovarian cancer (36,64,65), and FGF3/EGFR cooverexpression also was reported in NSCLC (77). In addition, the activation of FGFR autocrine pathways were found to be individually responsible for acquired resistance to gefitinib (an EGFR inhibitor) in NSCLC, and combination treatments such as PD173074 and gefitinib were required to restore effective growth inhibition (78,79). Likewise, EGFR/ErbBs recently were reported to limit the sensitivity to FGFR inhibition in FGFR3-mutated or -translocated cell lines such as RT112 (FGFR3/TACC3 fusion) and MGHU3 (Y375C) (80,81), and the PD173074 and gefitinib combination displayed an obvious synergistic effect (80).…”

Section: Discussionmentioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC

Cited by 175 publications

References 30 publications

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

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