Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I

MEK1/2 inhibitors (MEKi) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in PNF patients. We determined the efficacy of 6 different MEKi for treating PNFs, explored drug resistance mechanisms and identified potential combination therapies to overcome resistance. By screening drug efficacy among 6 MEKi in human NF1-deficient PNF cell lines, TAK-733 was found reduce PNF cell viability the most. We then cultured the TAK-733 resistant cells and explored potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors (CDKi) as potential agents for PNFs. Dinaciclib, a CDKi, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability, inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and CDK1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient-derived xenografts mouse models. Therefore, the combination of MEKi and CDKi may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant PNF patients. Overall design: The mRNA profiles of resistant and non-resistant PNF cell lines were generated by deep sequencing, in triplicate.