Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer
Menée à l'aide de lignées cellulaires d'adénocarcinome canalaire du pancréas, cette étude examine les programmes d'expression génique dépendants de MYC et impliqués dans la croissance tumorale liée à la protéine KRAS ou ERK
Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC. Gene expression programs directed by MYC mediate oncogenic KRAS signaling in pancreatic cancer. Mutations in the protein KRAS drive the growth of various cancers; thus, the gene expression programs induced by KRAS signaling are of particular interest for biomarker and drug development. Although oncogenic KRAS activates multiple transcription factors through the kinase ERK, Hibshman et al. found that MYC drove much of the mutant KRAS-dependent gene expression in pancreatic cancer (PDAC). MYC was critical for the proliferation of multiple KRAS-mutant PDAC cell lines, regulated several kinases, and induced a cell survival response through the small GTPase RHO. Because MYC itself is not yet druggable, the findings may inform new therapeutic strategies for PDAC. —Leslie K. Ferrarelli
Science Signaling , article en libre accès, 2025