Abstract C16: Mapping synthetic vulnerabilities in non-small cell lung cancer

Diversity in the genetic lesions that drive cancer initiation and progression is extreme. This diversity exists not only among tumors from different patients, but also among cancer cells within the same patient. This nefarious complexity is, in large measure, responsible for the capacity of this disease to evade current best efforts for effective therapy. “Personalized medicine” has been proposed in response to this conundrum as a mechanism to tailor cancer treatment to a specific tumor's genetic and epigenetic characteristics. However, selection of appropriate treatment is dramatically limited by the paucity of appropriate drugs and by the difficulty of linking treatment options to the appropriate patients. The challenge is to identify authentic intervention targets for development of an appropriately diverse cohort of therapies to contend with disease heterogeneity. We are addressing this challenge by a focused investigation of common vulnerabilities that arise as a consequence of oncogene expression and tumor evolution. Here we will describe a cancer intervention discovery pipeline using parallel genetic and chemical perturbations within an extensive panel of cell lines representative of the molecular lesions detected in lung cancer by national and international cancer genome sequencing efforts. We have found that current first line targeted therapies are discoverable within this panel together with the enrollment biomarkers required to stratify patient treatment regimens. Further, we have found that new genetic and chemical vulnerabilities can be revealed that are linked to recurrent mutations in lung cancer patients that are not currently “actionable”. We are leveraging this approach to stratify lung cancer subtypes and elaborate intervention targets that are linked to those subtypes by robust molecular discriminators. Note: This abstract was not presented at the conference. Citation Format: Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, Iryna Zubovych, Bo Yeun Seo, Jimi Kim, Banu Eskiocak, Hannah Chung, Elizabeth McMillan, Sherry Wu, Jef De Brabander, Kakajan Komurov, Bruce A. Posner, Rolf Brekken, Anil K. Sood, Ralph J. Deberardinis, Michael G. Roth, John D. Minna, Michael A. White. Mapping synthetic vulnerabilities in non-small cell lung cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C16.