Biomarker accessible and chemically addressable mechanistic subtypes of braf melanoma

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 YuJef K. De Brabander, Noelle S. Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael A. White

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)832-851
Number of pages20
JournalCancer discovery
Volume7
Issue number8
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Oncology

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    Eskiocak, B., McMillan, E. A., Mendiratta, S., Kollipara, R. K., Zhang, H., Humphries, C. G., Wang, C., Garcia-Rodriguez, J., Ding, M., Zaman, A., Rosales, T. I., Eskiocak, U., Smith, M. P., Sudderth, J., Komurov, K., Deberardinis, R. J., Wellbrock, C., Davies, M. A., Wargo, J. A., ... White, M. A. (2017). Biomarker accessible and chemically addressable mechanistic subtypes of braf melanoma. Cancer discovery, 7(8), 832-851. https://doi.org/10.1158/2159-8290.CD-16-0955