FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Guagnano, Vito; Kauffmann, Audrey; Wöhrle, Simon; Stamm, Christelle; Ito, Moriko; Barys, Louise; Pornon, Astrid; Yao, Yao; Li, Fang; Zhang, Yun; Chen, Zhi; Wilson, Christopher J.; Bordas, Vincent; Douget, Mickaël Le; Gaither, L. Alex; Borawski, Jason; Monahan, John E.; Venkatesan, Kavitha; Brümmendorf, Thomas; Thomas, David M.; García‐Echeverría, Carlos; Hofmann, Francesco; Sellers, William R.; Graus‐Porta, Diana

doi:10.1158/2159-8290.cd-12-0210

Cited by 304 publications

(292 citation statements)

References 35 publications

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“…S3). We found that 8p12 ( FGFR1 ) clustered together with the 11q13 ( CCND1 , FGF4 , FGF19 ) amplicon in some cases, a fi nding that has been recently associated with FGFR inhibitor sensitivity in the presence of beta-klotho expression ( 27 ). Most of the amplifi ed regions formed single clusters [e.g., 3q26 ( SOX2 ), 4q12 ( KIT , PDGFRA ), 8q24 ( MYC )] or were split into minor subclusters [7p11 ( EGFR ), 12q15 ( FRS2 ), 19q12 ( CCNE1 )].…”

Section: Research Articlementioning

confidence: 62%

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Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

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The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);

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Section: Research Articlementioning

confidence: 62%

“…33 (339) 4q12 (11) 5q15.2 (11) 5p12 (6) 7p11.2 (24) 8p12 (45) 8p24. 2 (20) 9p13.3 (29) 11p13.3 (27) 12p12.1 (27) 12p15 (19) 13p22.1 (0)…”

Section: Ligand Dependency Of Fgfr Signaling In Lung Tumor Cells Bearmentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

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“…Table 3). These results suggest FGFR1-gene amplification is important to predict sensitivity against FGFR inhibitors, and the apparent discrepancy may be a result of drug promiscuity; in contrast to NVP-BGJ398 and AZD4547 which are relatively selective pan-FGFR inhibitors 33,34 , Ponatinib inhibits a number of non-FGFR kinases with IC50 concentrations less than 10nM, including VEGFR, PDGFR, EPH receptors, SRC, KIT, and RET 35 .…”

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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“…By the high-throughput cell line profiling assay, amplifications or mutations of FGFR genes in cancer cell lines have been reported to predict sensitivity to the selective pan-FGFR inhibitor BGJ398. 25 This drug is currently in a phase I study in patients of advanced solid tumors with FGFR1/2 amplification or FGFR3 mutation (Novartis, Basel, Switzerland; ClinicalTrials.gov identifier: NCT01004224). Clinical investigations, akin to those conducted in other solid tumors with oncogenic fusion kinases, such as EML4-ALK, 26 are warranted to examine the efficacy of FGFR inhibitors for the treatment of defined subset of cholangiocarcinoma harboring FGFR2 fusions.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma

Arai¹,

Totoki²,

Hosoda³

et al. 2014

Hepatology

451

419

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Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation. Conclusion: FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease. (HEPATOLOGY 2014;59:1427-1434 C holangiocarcinoma (CC) is a highly malignant invasive carcinoma that arises through malignant transformation of cholangiocytes.1 It is an intractable tumor with poor prognosis, whose incidence and mortality rates are high in East Asia and have been rapidly increasing worldwide.1,2 CC can be subdivided into intrahepatic (ICC) and extrahepatic (ECC) types, which show distinct etiological and clinical features.2 ICC is the second most common primary hepatic malignancy after hepatocellular carcinoma, and is associated with hepatitis virus infection. Somatic mutations of KRAS and BRAF are the most common genetic alterations in CC.3,4 Surgical resection is the only curative treatment for CC, and no standard chemotherapy regimens have been established for inoperative cases or those showing recurrence after surgical resection. 5,6

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FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Cited by 304 publications

References 35 publications

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

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

Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma

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