Mutant HRAS as novel target for MEK and mTOR inhibitors
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Michael K. Kiessling1,2, Alessandra Curioni-Fontecedro2, Panagiotis Samaras2, Kirstin Atrott1, Jesus Cosin-Roger3, Silvia Lang1, Michael Scharl1, Gerhard Rogler1
1Division of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland
2Division of Oncology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland
3Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Valencia, Spain
Michael K. Kiessling, e-mail: [email protected]
Keywords: HRAS mutations, MEK inhibitor, mTOR inhibitor, lung cancer, bladder cancer
Received: March 23, 2015 Accepted: October 22, 2015 Published: November 03, 2015
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.
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