Abstract 963: Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma.

Abstract

Abstract Inhibitors targeting specific genomic alterations have revolutionized cancer therapy and dramatically improved patient outcomes; nonetheless, after a period response, patient tumors almost universally develop resistance to these inhibitors and recur. In the case of squamous cell carcinoma of the lung, it has been demonstrated that focal amplifications of the FGFR1 gene occur in at least 10% of patients and that a subset of these events are sensitive to FGFR targeted therapies. Here, we describe the generation of resistant clones of the cell line NCI-H2077 to several FGFR inhibitors with clinical potential. This cell line is a squamous lung line with a focal amplification of FGFR1 that demonstrates dependency in the presence of both small molecule inhibitors and knockdown of the FGFR1 protein. After generation of resistant clones, we performed RTK phosphorylation arrays in the presence and absence of inhibitor to determine whether there were changes in the activity of other kinases, and the lines were sequenced to determine whether secondary mutations in FGFR1 had arisen. Follow-up experiments were performed to determine alternative sensitivities of the resistant clones. These experiments contribute to our growing understanding of the resistance mechanisms that arise in response to kinase inhibitors, and it is our hope that they will benefit patients undergoing treatment for FGFR1-amplified lung squamous cell carcinoma. Citation Format: Rachel G. Liao, Andrey Sivachenko, Gad Getz, Amit Dutt, Peter S. Hammerman, Matthew Meyerson. Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2013-963