In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms.

ABSTRACT: Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upreg

SUBMITTER: Teh JLF 

PROVIDER: S-EPMC6858088 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature