Understanding the consequences of oncogenic mutations on FGFR signaling

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Project Summary/Abstract Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases (RTKs) normally involved in tissue repair, hematopoiesis, angiogenesis, and embryonic development; however, upon amplification and/or mutation they have been implicated in a number of cancer types, including non-small cell lung cancer (NSCLC) and more recently in adenoid cystic carcinoma (ACC). Small-molecule inhibitors of FGFRs have been developed and are in clinical trials for the treatment of NSCLC. Oncogenic mutations of FGFRs occur both independently of and in response to targeted inhibition. Drug resistance mutations are a devastating challenge with any targeted therapy, making it absolutely critical to have an understanding of resistance mechanisms before such inhibitors reach the clinic. A prevalent drug resistant mutant of FGFR1 is the V561M mutation, termed the gatekeeper mutation. Our lab has reported a 38-fold increase in the catalytic rate of V561M FGFR1 relative to the wild-type enzyme, and has recently uncovered evidence that this mutation drives the epithelial to mesenchymal transition (EMT), an important process in tumor metastasis, through modification of the downstream signaling of FGFR1. Using immunoblots, CyTOF (cytometry time of flight), and other cell-based assays, I propose to investigate the differences in downstream signaling driving the enhanced EMT observed in V561M FGFR1 relative to WT. The mechanistic insight I will gain regarding the gatekeeper mutation and its effects on EMT and signaling has critical implications for the development of future generations of inhibitors and in the use of combination therapies to treat cancer patients. As FGFRs continue to emerge as drivers of cancer, it is crucial to examine their roles in other cancer types. The Yarbrough lab (Yale University) has recently identified the amplification and mutation of FGFRs as potential drivers of adenoid cystic carcinoma (ACC), a rare disease that is partially driven through the formation of cancer stem cells (CSC). In collaboration with the Yarbrough lab, I propose to validate FGFR as a target for ACC therapy and to interrogate the role of a mutant FGFR2 in driving growth and/or stemness of ACC cells cultured directly from patient derived xenografts. I will use a variety of cell-based assays including immunoblots and CyTOF. ACC currently has no targeted therapy options; the validation of FGFR as a driver of tumor growth and CSC proliferation will be a huge step forward for the entire field of head and neck cancer treatment.