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MYC-dependent kinome in pancreatic cancer

ABSTRACT: 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 that genetic suppression of the MYC transcription factor alone phenocopied KRAS suppression in signaling, growth and metabolic processes. To establish a molecular basis for MYC support of KRAS-ERK-driven PDAC growth, we determined the gene transcription changes caused by acute loss of MYC function and identified 1,685 MYC-dependent (UP) and 1,325 MYC-inhibited (DN) genes. Dependency Map analyses demonstrated that MYC UP but not DN genes are essential for PDAC growth. Instead, pathway analyses support MYC DN genes as a secondary RHO GTPase-mediated compensatory response to oncogenic stress. We found that 36% of ERK-dependent genes are MYC-dependent, supporting the dominant role of MYC in driving ERK-regulated gene expression. Finally, proteomic profiling revealed that MYC regulated a complex kinome comprised of protein kinases that likely contribute to MYC-driven cancer growth. We conclude that MYC supports KRAS-ERK-dependent PDAC growth through regulation of a complex transcriptome and kinome.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Pancreatic Cancer

SUBMITTER: Clint Stalnecker

LAB HEAD: Channing Der

PROVIDER: PXD061413 | Pride | 2026-01-15

REPOSITORIES: Pride

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