Abstract B36: Modeling genetic mechanisms of resistance in melanoma primary tumor xenografts

Melanoma is the most lethal skin cancer and approximately 50% of the cases harbor mutations in the BRAF oncogene, with the mutation V600E representing 80-90% of all BRAF mutations in this indication. BRAF inhibitors as Vemurafenib and Dabrafenib have shown improved overall and progression free survival; however, the long term efficacy of these compounds is limited by the emergence of resistance. Several mechanisms of resistance to BRAF inhibitors have been already described, such as BRAF overexpression, increased ERBB3 signaling, expression of BRAF alternative isoforms, secondary mutations in BRAF or MEK1 and recently BRAF amplifications, among others. A fundamental aspect on devising optimal therapeutic regimes that overcome resistance is to develop preclinical models that resemble the genetic makeup of clinical patients who become resistance during the course of treatment to BRAF inhibitors. To this end, melanoma primary tumor xenografts (PTX) harboring BRAF V600E mutations were subject to treatment with BRAF inhibitors and response data was collected for a maximum of 180 days. Vehicle and treated samples were then sequenced using a targeted next generation sequencing approach in order to characterize their mutational landscape. Raw sequencing data was aligned to the human genome and potential mouse contamination was filter out before downstream analysis. Comparing SNV and copy number calls between treated and control samples revealed that focal amplifications of BRAF and de-novo mutations in the MEK1 gene were frequent genetic aberrations found in the PTX models that developed resistance. In summary, our results indicate that the genetic mechanisms of resistance observed in primary tumor xenograft models closely resemble what is observed in the clinical setting, making these models a valuable research tool for designing optimal therapeutic strategies. Citation Format: Alejandro Balbin, Angad Singh, Joshua Korn, Hui Gao, Darrin Stuart, John Green, Andrew Crenshaw, Scott Mahan, Nathan Houde, Alina Raza, Rebecca Leary, Derek Chiang, Michael Morrissey, Wendy Winckler, Sellers William. Modeling genetic mechanisms of resistance in melanoma primary tumor xenografts. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B36.