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Ref Type | Journal Article | ||||||||||||
PMID | (29437705) | ||||||||||||
Authors | Dolgikh N, Hugle M, Vogler M, Fulda S | ||||||||||||
Title | NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3Kα. | ||||||||||||
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Abstract Text | Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivoNRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kα-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kα-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000-13. ©2018 AACR. |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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NRAS mutant | leukemia | sensitive | Alpelisib + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Alpelisib (BYL719) and Binimetinib (MEK162) led to a synergistic effect in leukemia cells harboring mutant NRAS, demonstrating cell death in culture (PMID: 29437705). | 29437705 |
NRAS Q61H | rhabdomyosarcoma | sensitive | Alpelisib + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Alpelisib (BYL719) and Binimetinib (MEK162) led to a synergistic effect in rhabdomyosarcoma cells harboring NRAS Q61H, demonstrating cell death in culture (PMID: 29437705). | 29437705 |
NRAS mutant | neuroblastoma | sensitive | Alpelisib + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Alpelisib (BYL719) and Binimetinib (MEK162) led to a synergistic effect in neuroblastoma cells harboring mutant NRAS, demonstrating cell death in culture (PMID: 29437705). | 29437705 |