Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers

Abstract

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.

Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis In Vitro

“…As a KRAS mutated cell line, survival mechanisms are upregulated per se in Panc1 cells involving elevated Akt expression and activation [ 53 ]. In line with earlier studies by other groups, we also confirmed relatively high activated p-Akt/Ser473 levels in Panc1 cells using flow cytometry [ 54 , 55 ].…”

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer CellsIn VitroandIn Vivo

“…Activating mutations in Kras promote proliferation and survival through the RAF/MEK/ERK and PIK3/AKT pathways. Kras G12D mutations, as investigated in our study, are the most prevalent mutations in pancreatic cancer [46], but due to the inherent nature of the Ras protein, Ras inhibition has not resulted in relevant clinical benefit despite high prevalence of Ras mutations in pancreatic cancer. Therefore, therapies designed to specifically target downstream effectors have been developed (reviewed in [47]).…”

Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer

“…Targeting PDAC tumors with inhibitors of MEK, such as trametinib, has shown efficacy in pre-clinical models of PDAC, 10 , 11 although resistance is a frequent occurrence and toxicity issues have also resulted in limited success in clinical trials. 12 Inhibitors of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) have been shown to prevent adaptive resistance to MEK inhibitors in multiple cancer models, 13 , 14 and combinations of ERK and autophagy inhibitors have also demonstrated enhanced efficacy compared to single-agent treatments.…”