Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

Banu Eskiocak, Elizabeth McMillan, Saurabh Mendiratta, Rahul Kollipara, Hailei Zhang, Caroline Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy Rosales, Ugur Eskiocak, Michael P Smith, Jessica Sudderth, Kakajan Komurov, Ralph J DeBerardinis, Claudia Wellbrock, Michael A Davies, Jennifer A Wargo, Yonghao YuJef K De Brabander, Noelle S Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael White

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Abstract

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological 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 pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-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/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.

Original languageEnglish
JournalCancer discovery
Early online date28 Apr 2017
DOIs
Publication statusPublished - 2017

Keywords

  • Journal Article

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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