Abstract 457: FGFR1 overexpression is frequent in adult soft tissue sarcoma and predicts sensitivity to FGFR inhibitors

Abstract

Abstract Purpose: Soft-tissue sarcomas (STS) are highly diverse, devastating and clinically challenging malignancies. In advanced-stage STS, conventional chemotherapy provides symptom palliation but not prolonged survival, which typically ranges from 11-15 months after development of distant metastases. Thus, there is an urgent need for more effective, well-tolerated and targeted STS therapies. Alterations of the FGFR1 receptor tyrosine kinase are under investigation as biomarker of FGFR inhibitor sensitivity in several epithelial cancers. Prompted by the detection of high-level FGFR1 amplification in a patient with metastatic leiomyosarcoma through clinical exome sequencing, we investigated the role of FGFR1 as oncogenic driver and potential drug target in STS. Specific aims were to (i) determine the frequency of FGFR1 amplification and overexpression in adult STS, (ii) evaluate the sensitivity of FGFR1-altered STS cells to genetic and pharmacologic FGFR1 inhibition, and (iii) delineate the signaling pathways engaged by FGFR1 in these cells. Experimental design: The frequency of FGFR1 amplification and overexpression was established in a cohort of patients with treatment-näive high-grade STS using array-based comparative genomic hybridization and mRNA expression profiling, respectively, and results were validated using data from The Cancer Genome Atlas (TCGA). FGFR1 dependence was assessed in STS cell lines with and without FGFR1 alteration through RNA interference (RNAi)-mediated knockdown and selective small-molecule FGFR inhibitors. FGFR ligand and pharmacologic inhibitors were employed to dissect FGFR signaling in FGFR1-altered STS cells. Results: FGFR1 amplification and overexpression were present in 31% and 34% of cases in the untreated high-grade STS cohort (n = 176) and in 16% and 15% of cases in the TCGA cohort (n = 256). Interestingly, FGFR1 overexpression was detected in a substantial proportion of cases with no amplification (high-grade sarcoma cohort, 26%; TCGA cohort, 6.6%) comprising seven STS subtypes. Functional studies employing RNAi and different FGFR inhibitors (PD173074, AZD4547, BGJ398) demonstrated that the degree of dependence on FGFR1 for proliferation, survival, and anchorage-independent growth was primarily determined by FGFR1 expression levels. Furthermore, we identified the MAPK-ERK1/2 signaling axis as critical FGFR1 effector pathway whose suppression dictates the sensitivity of FGFR1-driven STS cells to FGFR-targeted therapy. Conclusions: FGFR1 amplification and overexpression are frequent events in multiple STS subtypes, and high FGFR1-expressing STS cells are sensitive to FGFR inhibition. These findings support FGFR1 as novel therapeutic target in STS and point to FGFR1 overexpression as a more reliable biomarker of sensitivity to FGFR pathway inhibition than genomic amplification, which might be of value for enrichment of future clinical trial populations. Citation Format: Priya Chudasama, Marcus Renner, Katja Specht, Sadaf Mughal, Barbara Hutter, Ingo Alldinger, Simon Schimmack, Dirk Jäger, Christof von Kalle, Stefan Gröschel, Stephan Wolf, Benedikt Brors, Wilko Weichert, Hanno Glimm, Gunhild Mechtersheimer, Claudia Scholl, Stefan Fröhling. FGFR1 overexpression is frequent in adult soft tissue sarcoma and predicts sensitivity to FGFR inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 457.