E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and MTOR-S6 Resistance Mechanisms

Overview

Journal Cancer Discov

Specialty Oncology

Date 2018 Mar 3

PMID 29496664

Citations 47

Authors

Jessica L F Teh

Phil F Cheng

Timothy J Purwin

Neda Nikbakht

Prem Patel

Inna Chervoneva

Adam Ertel

Paolo M Fortina

Ines Kleiber

Kim Hookim

Michael A Davies

Lawrence N Kwong

Mitch P Levesque

Reinhard Dummer

Andrew E Aplin

Affiliations

Soon will be listed here.

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 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, upregulation or mutation of was associated with resistance in models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. .

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