Mutant NRASQ61 shares signaling similarities across various cancer types – potential implications for future therapies
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Igor Vujic1,2, Christian Posch1,2, Martina Sanlorenzo1,3, Adam J. Yen1, Aaron Tsumura1, Andrew Kwong1, Valentin Feichtenschlager2, Kevin Lai1, Douglas V. Arneson1, Klemens Rappersberger2 and Susana M. Ortiz-Urda1
1 University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA
2 Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse, Vienna, Austria
3 Department of Medical Sciences, Section of Dermatology, University of Turin, Italy
Igor Vujic, email:
Keywords: NRAS, combination therapy, lung cancer, neuroblastoma
Received: May 07, 2014 Accepted: August 07, 2014 Published: August 08, 2014
Oncogenic mutations in the Neuroblastoma Rat Sarcoma oncogene (NRAS) are frequent in melanoma, but are also found in several other cancer types, such as lung cancer, neuroblastoma and colon cancer. We designed our study to analyze changes in NRAS mutant tumor cells derived from malignancies other than melanoma. A variety of small molecule inhibitors as well as their combinations was tested in order to find beneficial inhibitory modalities in NRASQ61mutant lung cancer and neuroblastoma cell lines. Signaling changes after incubation with inhibitors were studied and compared to those found in NRAS mutant melanoma.
All cell lines were most sensitive to inhibition in the MAPK pathway with the MEK inhibitor trametinib. MEK/AKT and MEK/CDK4,6 inhibitor combinations did not show any beneficial effects in vitro. However, we observed strong synergism combining MEK and PI3K/mTOR inhibitors in all cell lines. Our study provides evidence that NRAS mutant cancers share signaling similarities across different malignancies. We demonstrate that dual pathway inhibition of the MAPK and PI3K/AKT/mTOR pathway synergistically reduces cell viability in NRAS mutant cancers regardless of their tissue origin. Our results suggest that such inhibitor combinations may be a potential treatment option for non-melanoma tumors harboring activating NRAS mutations.
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