title: Mutant HRAS as novel target for MEK and mTOR inhibitors.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.|Division of Oncology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Kiessling
authors.affiliation: Division of Oncology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Curioni-Fontecedro
authors.affiliation: Division of Oncology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Samaras
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Atrott
authors.affiliation: Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Cosin-Roger
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001549:Benzamides; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C581313:binimetinib; C506614:mirdametinib; D004159:Diphenylamine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HRAS mutations; MEK inhibitor; bladder cancer; lung cancer; mTOR inhibitor