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J Clin Invest. 2018 Apr 2;128(4):1442-1457. doi: 10.1172/JCI94840. Epub 2018 Mar 5.

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
2
Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
3
Structural Biology Program, MSKCC, New York, New York, USA.
4
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
5
CRUK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
6
Department of Pathology, MSKCC, New York, New York, USA.
7
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
8
Department of Medicine, MSKCC, New York, New York, USA.

Abstract

Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in the degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.

KEYWORDS:

Cancer; Melanoma; Oncology; Signal transduction; Therapeutics

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