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Cancer Discov. 2018 May;8(5):568-581. doi: 10.1158/2159-8290.CD-17-0699. Epub 2018 Mar 1.

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

Author information

1
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland.
3
Department of Cutaneous Biology and Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
4
Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
6
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
7
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu.

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, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.Significance: 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. Cancer Discov; 8(5); 568-81. ©2018 AACR.See related commentary by Sullivan, p. 532See related article by Romano et al., p. 556This article is highlighted in the In This Issue feature, p. 517.

PMID:
29496664
DOI:
10.1158/2159-8290.CD-17-0699
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