biostudies-literatureBrannon AAmerican Cancer SocietyNIDDK NIH HHSNational Cancer InstituteNCI NIH HHSNational Institutes of HealthNIH HHSAmerican Association for Cancer Research11133https://www.ebi.ac.uk/biostudies/studies/S-EPMC7340786biostudies-literatureUnknown10(1)Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.Scientific reportsBeta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition.PMC7340786U01CA-224145127662-PF-15-033-01-DDC16-70-25-ABELP30 CA046592F31CA203563R01 CA198074P30 DK034933RO1CA151588U01 CA224145Schoettle SSteele NDrouillard DCrawford HCAbel EVPasca di Magliano MBrannon AfalseBeta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition.Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.2020-01-01T00:00:00Z2020 Jul2025-05-29T19:53:30.594Z2025-05-29T19:53:30.594ZS-EPMC73407863263640910.1038/s41598-020-67814-9