MAPK inhibition in BRAFV600 mutant melanoma patient derived xenografts

Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600 mutant melanoma. However, the duration and depth of response vary significantly between patients, therefore predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of a MITF-high, ‘epithelial-like’ transcriptional program is associated with adaptive response and intrinsic resistance. On the other hand, xenograft models that express a MAPK-driven ‘mesenchymal-like’ transcriptional program are preferentially sensitive to MAPK inhibition. These gene expression programs are somewhat similar to the MITF high and low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with sensitivity. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600 mutant melanoma rely on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predict their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the inter-tumor heterogeneity in BRAFV600 mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.