Patients with non-small cell lung cancer (NSCLC) display a wide spectrum of oncologic outcomes, suggesting significant underlying biologic diversity. Despite two notable exceptions in the cases of EGFR mutations and ALK rearrangements, current therapeutic management is largely homogeneous for a given stage. To advance genotype-directed therapy in NSCLC, we sought to identify genetic determinants of therapeutic resistance by leveraging cancer genomic data with a recently developed high-throughput platform for measuring radiation survival (Cancer Res. 2013. 73(20): 6289-98). To adequately represent the biologic spectrum of lung cancer and maximize power to detect clinically relevant genotypes, we profiled 104 lung cancer cell lines, including 89 NSCLC and 15 small cell lung cancer (SCLC) lines. We used our recently validated high-throughput proliferation assay to measure survival. Genomic correlates of radiosensitivity were explored by accessing Oncomap data from the Cancer Cell Line Encyclopedia, the COSMIC database of the Cancer Genome Project, and The Cancer Genome Atlas. Radiation survival across lineages reflected clinical experience and the literature regarding differential response to radiation, inasmuch as lung squamous cell carcinoma and adenocarcinoma (ACA) had similar radiosensitivity, whereas SCLC was less radiosensitive. Importantly, radiosensitivity varied more within a lineage than across lineages, with a 6-fold difference in integral survival among ACA lines. Correlation with cancer genomic data revealed clustering of BRAF mutations within the most resistant ACA lines (p = 0.035). When radiation survival distributions were compared by mutation status, BRAF-mutant ACA lines were significantly more resistant than BRAF wild-type ACA lines (p = 0.023). Some of the mutations identified by our analysis have been previously annotated by The Cancer Genome Atlas lung adenocarcinoma dataset and others appear to be novel. The identified BRAF mutations located in the highly conserved kinase domain enhanced kinase activity in a fashion analogous to the well-known BRAF V600E mutation. Integration of high-throughput radiation survival profiling with large-scale cancer genomic data suggests BRAF mutations are associated with therapeutic resistance in lung ACA. Our analysis nominates BRAF pathway inhibitors, which are commercially available, as therapeutic sensitizers in select BRAF-mutant lung ACA. Further investigation has the potential to yield an additional genotype-directed therapy that could impact up to 7% of patients with lung ACA, a prevalence comparable to that of ALK rearrangements (4%) or EGFR mutations (10%).

Citation Format: Mohamed Abazeed, Brian Yard, Drew Adams, Pablo Tamayo, Jason Hearn, Eui Kyu Chie, Stuart Schreiber, Matthew Meyerson, Craig Peacock, Peter Hammerman. Functional genomic profiling of lung adenocarcinoma identifies BRAF mutations as novel therapeutic targets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3315. doi:10.1158/1538-7445.AM2015-3315