Identifying the mechanisms of resistance to MEK inhibition to pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease for which no effective systemic therapy is currently available. PDAC is a \u201cKRAS-driven\u201d cancer as activating mutations of the GTPase are almost universal and proved necessary for the initiation and maintenance of PDAC in genetically-engineered mouse models of the disease. Despite representing an attractive pharmacological target, no direct KRAS inhibitor reached the clinic to date and most efforts have therefore focused on targeting essential nodes downstream of KRAS signalling, including the MAP kinase cascade. Based on previous reports, monotherapy with MAP Kinase inhibitors are predicted to be ineffective due to the activation of complex feedback loop mechanisms that lead to bypass resistance. Here, we used different models of PDAC to identify molecular determinants of adaptive resistance to inhibition of MAP Kinase using an allosteric MEK1/2 inhibitor (trametinib, MEKi). We showed that PDAC cells lines that align with the squamous/basal-like subtype are more resistant to MEKi as compared to cells representative of the pancreatic progenitor/classical subtype. Regardless of the subtype, our integrative RNAseq and phosho-proteomic approach identified activation of FGFR3 as mechanisms used by PDAC cells to overcome MEK1/2 blockade and maintain the index oncogenic signalling output. MEKi-induced transcriptional upregulation of FGFR3 was also evident in mouse PDAC isografts treated continuously with MEKi. We further performed in silico analysis, through the Connectivity Map database, and in vitro drug-testing to demonstrate that FGFR inhibition sensitize PDAC cells to MEK inhibition. Taken together, our data strongly suggest combined inhibition of MEK and FGFR3 as potential treatment for PDAC regardless of the subtype