Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
Year: 2017
Type: article
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. 799. This article is highlighted in the In This Issue feature, p. 783
Source: Cancer Discovery
Authors: Banu Eskiocak, Elizabeth A. McMillan, Saurabh Mendiratta, Rahul K. Kollipara, Hailei Zhang, Caroline G. Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy I. Rosales, Ugur Eskiocak, Michael P. Smith, Jessica Sudderth, Kakajan Komurov, Ralph J. Deberardinis, Claudia Wellbrock, Michael A. Davies, Jennifer A. Wargo, Yonghao Yu, Jef K. De Brabander, Noelle S. Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael A. White
Institutions: The University of Texas Southwestern Medical Center, Broad Institute, Massachusetts Institute of Technology, Wellcome Centre for Cell-Matrix Research, University of Manchester, Cincinnati Children's Hospital Medical Center, The University of Texas MD Anderson Cancer Center, The University of Sydney
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G2265115783, G3207250158, G4078215661, Lung cancer oncogenotype-selective drug target discovery, Targeting Mechanistic Subtypes of Neoplastic Disease, Exploring synergy of combined BRAF-targeted therapy & immunotherapy for melanoma, UT Southwestern Medical Center Simmons Comprehensive Cancer Center, The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
OpenAlex ID: W2608258698