AP1/Fra1 confers resistance of pancreatic cancer cells to inhibitors of the MAPK cascade

Targeting oncogenic KRAS downstream signaling remains an important therapeutic opportunity in pancreatic ductal adenocarcinoma (PDAC). To decipher transcriptional integrators of oncogenic KRAS, we used primary pancreatic ductal epithelial cells (PDECs) allowing for the time-specific expression of KrasG12D driven from the endogenous promoter. We show that the AP1 family member FRA1 is tightly connected to the KRAS signal. Although FRA1 is highly expressed in pre-malignant lesions and the basal-like subtype of human PDACs, the FRA1 gene is dispensable for murine KrasG12D-induced PanIN formation and PDAC development. Using isogenic FRA1 gain- and loss-of-function in an unbiased drug screen, we observed that FRA1 is an important modulator of the responsiveness of PDAC cells to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, FRA1-associated adaptive rewiring of oncogenic ERK signaling is rendering FRA1-deficient cells sensitive to inhibitors of the canonical KRAS driven signaling pathway. Furthermore, pharmacological induced degradation of FRA1 increases MEK inhibitor sensitivity. Therefore, the inactivation of FRA1 synergizes with inhibitors of canonical KRAS downstream signaling, allowing the development of rational and mechanism-based combination therapies.