Despite the development of potent RAF-MAPK pathway inhibitors, only a fraction of BRAF-mutant patients responds to the treatment with these drugs. Here, we applied a combined chemo-genomics and chemo-proteomics approach to gain insights into the dynamics of primary resistance signaling and to define novel cancer vulnerabilities in these tumors. These analyses uncovered differential pathway resiliency in response to MAPK inhibition in BRAF-mutant cancer cells. Using forward- and reverse-genetics we identify the assembly of RAS/RAF/MEK complexes as a critical force to override RAF-MAPK pathway inhibitor efficacy. Mapping of global phosphorylation dynamics using orthogonal mass-spectrometry based methods revealed multi-layered MAPK pathway feedback-loop release that feeds into MAPK-pathway hyperactivation. The phosphoprotein nuclear interacting partner of ALK (NIPA) identified in the phosphoproteome screen is critical for maintenance of the primary resistance phenotype. Overall, our data provide a kinome- and phosphoproteome-wide view of the adaptive process of primary resistance to MAPK inhibitors in BRAF-mutant tumors and reveals translatable strategies toward improvement of the efficacy of individualized therapies in these patients.

Citation Format: Martin L. Sos, Rebecca Levin, John Gordan, Juan Oses-Prieto, James Webber, Megan Salt, Byron Hann, Alma Burlingame, Frank Mccormick, Sourav Bandyopadhyay, Kevan Shokat. Integrated analysis of differential pathway resiliency in response to MAPK inhibition in BRAF-mutant cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-216. doi:10.1158/1538-7445.AM2014-LB-216