Mutant HRAS as novel target for MEK and mTOR inhibitors

Michael K Kiessling; Alessandra Curioni-Fontecedro; Panagiotis Samaras; Kirstin Atrott; Jesus Cosin-Roger; Silvia Lang; Michael Scharl; Gerhard Rogler

doi:10.18632/oncotarget.5619

Mutant HRAS as novel target for MEK and mTOR inhibitors

Oncotarget. 2015 Dec 8;6(39):42183-96. doi: 10.18632/oncotarget.5619.

Authors

Michael K Kiessling^{1

2}, Alessandra Curioni-Fontecedro², Panagiotis Samaras², Kirstin Atrott¹, Jesus Cosin-Roger³, Silvia Lang¹, Michael Scharl¹, Gerhard Rogler¹

Affiliations

¹ Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
² Division of Oncology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
³ Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Valencia, Spain.

Abstract

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an impact on viability. However, inhibition of mTOR or combined inhibition of MEK and mTOR reduced cell growth in a synergistic manner. Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition. Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.

Keywords: HRAS mutations; MEK inhibitor; bladder cancer; lung cancer; mTOR inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Benzamides / pharmacology
Benzimidazoles / pharmacology
Blotting, Western
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cell Transformation, Neoplastic / drug effects
Cell Transformation, Neoplastic / genetics
Diphenylamine / analogs & derivatives
Diphenylamine / pharmacology
Humans
Mice, SCID
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinase Kinases / metabolism
Mutation
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
RNA Interference
Signal Transduction / drug effects
Signal Transduction / genetics
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays

Substances

AZD 6244
Benzamides
Benzimidazoles
Protein Kinase Inhibitors
binimetinib
mirdametinib
Diphenylamine
MTOR protein, human
TOR Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
HRAS protein, human
Proto-Oncogene Proteins p21(ras)