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|Ref Type||Journal Article|
|Authors||Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, Chong K, Peng L, Dimon MT, Phillips T, Daud AI, McCalmont TH, LeBoit PE, Ortiz-Urda S|
|Title||Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo.|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date||2013 Mar 5|
|Abstract Text||Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|NRAS Q61L||melanoma||sensitive||CCT241161||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CCT241161 inhibited MEK and ERK activation and growth of a melanoma cell line harboring NRAS Q61L in culture, and inhibited tumor growth in a NRAS Q61L-mutant melanoma cell line xenograft model (PMID: 25500121, PMID: 23431193).||25500121 23431193|
|NRAS Q61L||melanoma||sensitive||CCT196969||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CCT196969 inhibited MEK and ERK activation and growth of a melanoma cell line harboring NRAS Q61L in culture, and inhibited tumor growth in a NRAS Q61L-mutant melanoma cell line xenograft model (PMID: 25500121, PMID: 23431193).||25500121 23431193|
|NRAS Q61L||melanoma||resistant||PLX4720||Preclinical - Cell line xenograft||Actionable||In a preclinical study, PLX4720 did not inhibit growth of melanoma cells harboring NRAS Q61L in culture or in cell line xenograft models (PMID: 25500121, PMID: 23431193).||25500121 23431193|