The molecular mechanism underlying KRAS regulation on STK31 expression in Pancreatic ductal adenocarcinoma

Abstract KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC) but targeting mutant KRAS is still challenging. Kinase inhibitors are ideal targeted therapeutics for mutant KRAS-driven cancer. In our study, an esiRNA screening was performed to identify kinases that play a critical role in KRAS mutant driven PDAC. STK31 was identified as a potential therapeutic target for KRAS mutant PDAC. In this study, we aimed to investigate the underlying mechanism of STK31 in KRAS mutant PDAC and its therapeutic potential. Our results showed that STK31 was upregulated in KRAS mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRAS G12D mutant background. Inhibition of STK31 in KRAS mutant cell lines significantly reduced PDAC cell growth and hindered in vivo tumor growth. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. Pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c-Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. By analyzing RNA sequencing data, we found cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Our results indicate that STK31 promotes PDAC cell growth by regulating the KRAS/MAPK/ERK/c-Jun signaling pathway and its impact on cell cycle regulator CCNB1.