Abstract 2999: Targeted depletion of all somatically mutated genes in lung cancer cells facilitates identification of mutationally activated novel drivers of lung cancer.

Approximately 70% of all NSCLC patients present with late stage disease (stage III-IV) and there is a pressing need to develop better therapies for these patients. This remains a major challenge as the underlying genetic causes of nearly half of all NSCLCs remain unknown. Recent success with therapies targeting mutationally activated EGFR and constitutively active EML4-ALK serve as proof of principle that drugs targeting genetically activated drivers of lung cancer result in better, more durable therapeutic responses in patients. In an effort to identify novel mutationally activated drivers of lung cancer, we performed a targeted siRNA screen to knockdown all somatically mutated genes in a panel of six NSCLC cell lines. Using this approach we have identified three mutationally activated drivers that include MLK1, PAK7 and FGFR4. We demonstrate that mutations in these genes are activating, that the cancer cells that harbour the genetically activated oncogenes rely on these drivers to maintain cell proliferation and survival and inhibition of these activated kinases results in specific killing of the lung cancer cells. As cancer genomic data accumulates at an unprecedented rate, approaches must be developed to filter through this data to identify druggable drivers that could lead to better therapeutic options for patients in the clinic. Our studies demonstrate that combining targeted siRNA screens with cancer genomics will be a successful approach to identify novel drivers of cancer. Citation Format: Shameem Fawdar, Eleanor W. Trotter, Yaoyong Li, Sara Ientile, Crispin Miller, John Brognard. Targeted depletion of all somatically mutated genes in lung cancer cells facilitates identification of mutationally activated novel drivers of lung cancer. [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 2999. doi:10.1158/1538-7445.AM2013-2999