AbstractPancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. The high mortality rate can be attributed to multiple factors, including late diagnosis and lack of effective therapies. 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 using primary mouse and human 3D organoid cultures. We optimized the culture of pancreatic tumor organoids that utilized Matrigel as a basement membrane mimetic, facilitating polarized growth. Pancreatic tumor organoids recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the organoids 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.
Beta 1 Integrin Signaling Mediates Pancreatic Ductal Adenocarcinoma Resistance to MEK Inhibition
