Pancreatic cancer is an increasing cause of
cancer related death worldwide. KRAS is the dominant oncogene in this
cancer type and molecular rationale would indicate, that inhibitors of the downstream target
MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular
biomarkers that can help to define subgroups where
MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three
pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical
pancreatic cancer samples to identify the molecular subtypes of
pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to
kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single
MEK inhibitor (
trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single
MEK inhibitors fails. However, combination of
MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression
MEK inhibitor induced Akt phosphorylation leads to
trametinib resistance which necessitates for
MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit
MEK inhibitor
therapy in
pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of
pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from
MEK inhibitor monotherapy.