p38gamma MAPK is essential for aerobic glycolysis and pancreatic tumorigenesis.

KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here we report that p38gamma MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38gamma interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38gamma increased expression of PFKFB3 and glucose transporter GLUT2; conversely, silencing mutant KRAS and p38gamma decreased PFKFB3 and GLUT2 expression. p38gamma phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout (KO) of p38gamma decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38gamma to stimulate glycolysis and PDAC growth and p38gamma required PFKFB3/S467 to promote these activities. A p38gamma inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38gamma. Moreover, overexpression of p38gamma, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38gamma links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38gamma and PFKFB3 may be targeted for therapeutic intervention in PDAC.