<i>NRAS</i>-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K<b>α</b>.

Abstract

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 <i>NRAS</i>-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in <i>NRAS</i>-mutated RMS cells <i>in vitro</i> and <i>in vivo</i><i>NRAS</i>- or <i>HRAS</i>-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than <i>RAS</i> wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in <i>NRAS</i>-mutated than <i>RAS</i> wild-type RMS tumors <i>in vivo</i> 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 <i>RAS</i>-mutated RMS.<b>Significance:</b> 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. <i>Cancer Res; 78(8); 2000-13. ©2018 AACR</i>.