Efficacy of the MEK1/2 inhibitor trametinib in combination with clinically-investigated γ-secretase inhibitors in rhabdomyosarcoma

The childhood muscle cancer rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In the last 40 years, outcomes for low and intermediate risk patients have improved; however, high risk patients with metastatic disease still have poor overall survival. Differentiation therapy for RMS has been considered a potential clinical approach to halting tumor progression by inducing the terminal myogenic differentiation program, and thus reducing the need for cytotoxic chemotherapy. Both the NOTCH and MEK pathway have been shown to play varying roles in inducing differentiation in RMS cells. Here, we tested several different RMS cell lines harboring varying genetic abnormalities with the MEK inhibitor trametinib alone, and in combination with {gamma}-secretase inhibitors and found no significant effect on cell viability when used together.