title: Mutant NRASQ61 shares signaling similarities across various cancer types--potential implications for future therapies.
abstract: 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.
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA. Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Vujic
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA. Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Posch
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA. Department of Medical Sciences, Section of Dermatology, University of Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sanlorenzo
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Yen
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Tsumura
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kwong
authors.affiliation: Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Valentin
authors.initials: V
authors.lastname: Feichtenschlager
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lai
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Arneson
authors.affiliation: Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rappersberger
authors.affiliation: University of California San Francisco, Mt. Zion Cancer Research Center, San Francisco, USA.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Ortiz-Urda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human