MEK1/2 in Rhabdomyosarcoma

Abstract

Alveolar and embryonal rhabdomyosarcoma (RMS) are soft-tissue cancers that affect children, adolescents, and young adults. Sometimes referred to as muscle cancer, RMS is a cancer of muscle and non-muscle origin that phenocopies incompletely differentiated myoblasts or activated satellite (muscle stem) cells. Interestingly, embryonal RMS (ERMS) has been observed to undergo terminal myogenic differentiation in response to stress induced by chemotherapy and radiation therapy4, 9, 24. Given the propensity of rhabdomyosarcoma to differentiation, in this report we explore the use of differentiation therapy combining MEK inhibitor (MEKi) cobimetinib and chemotherapy as a strategy to halt RMS growth. We evaluated a representative panel of RMS cell lines with cobimetinib and chemotherapy in two dosing schedules that mimic clinical use followed by cell growth evaluation and high content analysis (differentiation) assays. We uncovered that cobimetinib does not have significant additive or synergistic effects on cell differentiation or cell growth with chemotherapy in RMS and can have unanticipated antagonistic effects; specifically, pre-exposure of cobimetinib to cells can decrease the effectiveness of chemotherapy-mediated cell growth inhibition in vitro. Although differentiation-therapy is still a potential viable strategy in RMS, our data do not support MEKi/chemotherapy co-treatment in this context.