The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.

Abstract

Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.

• Authors: Eliezer M Van Allen, Nikhil Wagle, Antje Sucker, Daniel J Treacy, Cory M Johannessen, Eva M Goetz, Chelsea S Place, Amaro Taylor-Weiner, Steven Whittaker, Gregory V Kryukov, Eran Hodis, Mara Rosenberg, Aaron McKenna, Kristian Cibulskis, Deborah Farlow, Lisa Zimmer, Uwe Hillen, Ralf Gutzmer, Simone M Goldinger, Selma Ugurel, Helen J Gogas, Friederike Egberts, Carola Berking, Uwe Trefzer, Carmen Loquai, Benjamin Weide, Jessica C Hassel, Stacey B Gabriel, Scott L Carter, Gad Getz, Levi A Garraway, Dirk Schadendorf, Dermatologic Cooperative Oncology Group of Germany (DeCOG)
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 1 Pg. 94-109 (Jan 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 24265153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Indoles
• Oximes
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Sulfonamides
• Vemurafenib
• MAP2K2 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• dabrafenib

Topics

• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Exome
• Female
• HEK293 Cells
• Humans
• Imidazoles (therapeutic use)
• Indoles (therapeutic use)
• MAP Kinase Kinase 1 (genetics)
• MAP Kinase Kinase 2 (genetics)
• Male
• Melanoma (drug therapy, genetics)
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Oximes (therapeutic use)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Sequence Analysis, DNA
• Skin Neoplasms (drug therapy, genetics)
• Sulfonamides (therapeutic use)
• Vemurafenib