Distinct Transcriptional Programming Drive Response to MAPK Inhibition in -Mutant Melanoma Patient-Derived Xenografts.

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