NRAS-mutated rhabdomyosarcoma cells are vulnerable to mitochondrial apoptosis induced by co-inhibition of MEK and PI3K{alpha}

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 co-inhibition 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 vivo. NRAS or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wildtype, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wildtype 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 pro-apoptotic re-balancing 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.

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