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Cancer Discov. 2017 Aug;7(8):832-851. doi: 10.1158/2159-8290.CD-16-0955. Epub 2017 Apr 28.

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma.

Author information

1
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas.
2
Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas.
3
The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas.
5
Children's Research Institute and the Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas.
6
Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Manchester, United Kingdom.
7
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
8
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Melanoma Institute, University of Sydney, Sydney, New South Wales, Australia.
12
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas. michael.white@utsouthwestern.edu.

Abstract

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKε inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKε inhibitor-sensitive disease among nonresponders to current targeted therapy.Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKε inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832-51. ©2017 AACR.See related commentary by Jenkins and Barbie, p. 799This article is highlighted in the In This Issue feature, p. 783.

PMID:
28455392
PMCID:
PMC5540806
DOI:
10.1158/2159-8290.CD-16-0955
[Indexed for MEDLINE]
Free PMC Article

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