Enhancing targeted therapy of tumors with activating FGFR alterations.

e23134 Background: Emerging evidence points to the Fibroblast Growth Factor Receptor (FGFR) kinase family as a promising target in multiple cancer types including lung squamous cell carcinoma, cholangiocarcinoma, gastric, bladder and breast cancer. Although several FGFR kinase inhibitors have entered clinical trials, single agent clinical efficacy has been modest and resistance invariably occurs. A comprehensive understanding of the molecular basis of resistance to FGFR inhibitors is urgently needed to enable the successful application of anti-FGFR therapy in the clinic. Methods: We utilized a systematic genome-wide open reading frame (ORF) screen to identify genes whose upregulation confers resistance to the FGFR inhibitors BGJ398 and FIIN-3 in FGFR1-amplified H2077 lung cancer cells. In an orthogonal approach, we established resistant clones of FGFR1-amplified and FGFR3-translocated cell lines by chronic exposure to BGJ398, and characterized these by high-throughput gene expression analysis. Results: We identified 34 candidate genes, including expected findings such as a mutant KRAS allele and MET overexpression. Intriguingly, we also identified novel candidate resistance mechanisms involving the genes of the TAM family, which encode the transmembrane receptors Tyro3, Axl and Mertk. These tyrosine kinases may serve as a secondary target to augment FGFR therapy. We validated that the TAM family confers resistance to FGFR inhibitors in different FGFR dependencies including FGFR1-amplified lung cancer, FGFR2-amplified gastric and colon cancer and FGFR 3-translocated bladder cancer, with AXL having the greatest rescue. Notably, gene profiling of resistant clones also implicates the TAM family, with both receptors and their ligands upregulated in the majority cases. Moreover, concurrent TAM blockade augments the response to FGFR inhibition in vitro and provides a promising therapeutic strategy to overcome resistance. Conclusions: TAM kinases are important mediators of resistance to FGFR inhibitors and the dual blockade of FGFR and TAM provides a novel approach to enhance the efficacy of anti-FGFR therapy.