Abstract
Abstract Targeting cyclin dependent kinases 4 and 6 (CDK4/6) represents a viable therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor in different genetic subsets of melanoma. However, continuous dosing of MEK inhibitor (MEKi) plus CDK4/6 inhibitor (CDK4/6i) elicits toxicities in patients. Utilizing an in vivo E2F reporter system, we analyzed the efficacy of MEKi plus CDK4/6i schedules in a quantitative and temporal manner. Continuous MEKi with intermittent CDK4/6i led to more complete responses as compared to either continuous CDK4/6i with intermittent MEKi or intermittent dosing of both drugs. Nevertheless, some tumors acquired resistance. Phospho-proteomic analysis of resistant tumors revealed increased phosphorylation of ribosomal S6 protein (RPS6). These data were supported by staining of patient biopsies from clinical trials, which also indicated that high phospho S6 levels may serve as a predictor of response to CDK4/6i plus targeted inhibitors. Enhanced phospho S6 provided a therapeutic window for the mTORC1/2 inhibitor, AZD2014, in MEKi plus CDK4/6i-resistant tumors. Mechanistically, aberrant regulation of NRAS was associated with resistance and sufficient to mediate resistance. This study highlights the use of an in vivo reporter model for optimization of schedules and supports targeting the mTORC1/2-S6 pathway as a salvage option to overcome MEKi plus CDK4/6i resistance. Citation Format: Jessica Teh, Phil F. Cheng, Timothy J. Purwin, Neda Nikbakht, Prem Patel, Inna Chervoneva, Ines Keibler, HooKim Kim, Michael A. Davies, Lawrence N. Kwong, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2304.
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