Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers

Diána Brauswetter, Bianka Gurbi, Attila Varga, Edit Várkondi, Richárd Schwab, G. Bánhegyi, Orsolya Fábián, G. Kéri, István Vályi-Nagy, I. Peták

Research output: Article

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e0185687
JournalPLoS One
Volume12
Issue number9
DOIs
Publication statusPublished - jan. 1 2017

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pancreatic neoplasms
Mitogen-Activated Protein Kinase Kinases
Pancreatic Neoplasms
cell lines
Cells
Cell Line
mutation
cell viability
Mutation
neoplasms
oncogenes
Cell Survival
clinical trials
biomarkers
phosphorylation
phosphotransferases (kinases)
Phosphorylation
Western blotting
Biomarkers
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. / Brauswetter, Diána; Gurbi, Bianka; Varga, Attila; Várkondi, Edit; Schwab, Richárd; Bánhegyi, G.; Fábián, Orsolya; Kéri, G.; Vályi-Nagy, István; Peták, I.

In: PLoS One, Vol. 12, No. 9, 01.01.2017, p. e0185687.

Research output: Article

Brauswetter, D, Gurbi, B, Varga, A, Várkondi, E, Schwab, R, Bánhegyi, G, Fábián, O, Kéri, G, Vályi-Nagy, I & Peták, I 2017, 'Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers', PLoS One, vol. 12, no. 9, pp. e0185687. https://doi.org/10.1371/journal.pone.0185687
Brauswetter D, Gurbi B, Varga A, Várkondi E, Schwab R, Bánhegyi G et al. Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. PLoS One. 2017 jan. 1;12(9):e0185687. https://doi.org/10.1371/journal.pone.0185687
Brauswetter, Diána ; Gurbi, Bianka ; Varga, Attila ; Várkondi, Edit ; Schwab, Richárd ; Bánhegyi, G. ; Fábián, Orsolya ; Kéri, G. ; Vályi-Nagy, István ; Peták, I. / Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. In: PLoS One. 2017 ; Vol. 12, No. 9. pp. e0185687.
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