Defining the role of MYC in KRAS-mutant pancreatic cancer

We recently established the ERK-dependent transcriptome and phosphoproteome in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). Of 1,718 ERK-dependent genes, 143 encode transcription factors. Of 2,123 ERK-dependent phosphoproteins, 98 are transcription factors. Despite this complexity, we observed here that genetic suppression of the MYC transcription factor alone phenocopied KRAS suppression in signaling, growth, and metabolic processes. To explore why, we determined the gene transcription changes caused by acute suppression of MYC function and identified 1,685 MYC-dependent (UP) and 1,325 MYC-inhibited (DN) genes. Dependency Map and pathway analyses suggest that MYC UP genes comprise the bulk of the MYC-regulated genes that are essential for PDAC growth, and that MYC DN genes may comprise a compensatory response to oncogenic stress mediated in part by RHO GTPase signaling. We found that 36% of ERK-dependent genes are MYC-dependent in PDAC cells, supporting the dominant role of MYC in driving ERK-regulated gene expression. Finally, proteomic profiling revealed that MYC regulates a complex kinome comprised of protein kinases that likely contribute to MYC-driven cancer growth and can be targeted therapeutically. Together, these data provide a comprehensive molecular portrait of MYC-dependent signaling, with therapeutically exploitable mechanisms for treating PDAC.