MEK Inhibition Induces Differentiation in RAS-Driven Rhabdomyosarcoma

Fusion-negative rhabdomyosarcomas (FN-RMS), which lack PAX3/7 gene rearrangements, arise from skeletal muscle precursor cells that fail to differentiate despite expression of the myogenic master transcription factor MYOD1. These tumors commonly harbor mutations in RAS isoforms (NRAS, HRAS, or KRAS), but the role of RAS in FN-RMS differentiation blockade and tumorigenesis has not been well described. Yohe, Gryder, and colleagues performed a high-throughput drug screen to discover compounds that selectively target FN-RMS cells. Oncogenic RAS was required for FN-RMS survival and activated the MAPK pathway to block myoblast differentiation and, consistent with these findings, the MEK inhibitor trametinib selectively reduced FN-RMS cell viability, upregulated the prodifferentiation myogenic transcription factor MYOG, and induced myogenic differentiation. Mechanistically, ERK2 bound to myogenic differentiation genes, including the promoter of MYOG, where it phosphorylated RNA Pol II, resulting in RNA Pol II stalling and transcriptional repression. MEK inhibition resulted in release of ERK2 from the MYOG promoter, facilitating MYOG transcription. Trametinib treatment also resulted in MYOG-dependent chromatin remodeling, resulting in open chromatin and establishment of superenhancers at genes required for late myogenic differentiation (including MYH3). In vivo, MEK inhibition induced differentiation to suppress the growth of RAS-mutant RMS xenografts. To find possible drug combinations that might improve therapeutic efficacy, a combinatorial drug screen was performed. The IGF1R inhibitor BMS-754807 synergized with trametinib to induce tumor regression in mice with RAS-driven RMS. In addition to uncovering a mechanism by which RAS signaling suppresses MYOG expression to block MYOG-dependent chromatin remodeling and cellular differentiation in FN-RMS, these findings suggest that patients with FN-RMS may benefit from combination therapy with MEK and IGF1R inhibitors.

Yohe ME, Gryder BE, Shern JF, Song YK, Chou HC, Sindiri S, et al. MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med 2018;10:eaan4470.

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