Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
Jeffrey A KlompJennifer E KlompClint A StalneckerKirsten L BryantA Cole EdwardsKristina Drizyte-MillerPriya S HibshmanJ Nathaniel DiehlYe S LeeAlexis J MoralesKhalilah E TaylorSen PengNhan L TranLaura E HerringAlex W PrevatteNatalie K BarkerLaura D HoverJill HallinSaikat ChowdhuryOluwadara CokerHey Min LeeCraig M GoodwinPrson GautamPeter OlsonJames G ChristensenJohn Paul ShenEdmund S KopetzLee M GravesKian-Huat LimAndrea Wang-GillamKrister WennerbergAdrienne D CoxChanning J DerPublished in: Science (New York, N.Y.) (2024)
How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.