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Proc Natl Acad Sci U S A. 2019 Feb 19. pii: 201821889. doi: 10.1073/pnas.1821889116. [Epub ahead of print]

Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by activating MAP kinase pathway.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
2
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; narendra.wajapeyee@yale.edu michael.green@umassmed.edu.
3
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240.

Abstract

Acquired resistance to BRAF kinase inhibitors (BRAFi) is the primary cause for their limited clinical benefit. Although several mechanisms of acquired BRAFi resistance have been identified, the basis for acquired resistance remains unknown in over 40% of melanomas. We performed a large-scale short-hairpin RNA screen, targeting 363 epigenetic regulators and identified Block of Proliferation 1 (BOP1) as a factor the loss of which results in resistance to BRAFi both in cell culture and in mice. BOP1 knockdown promoted down-regulation of the MAPK phosphatases DUSP4 and DUSP6 via a transcription-based mechanism, leading to increased MAPK signaling and BRAFi resistance. Finally, analysis of matched patient-derived BRAFi or BRAFi+MEKi pre- and progressed melanoma samples revealed reduced BOP1 protein expression in progressed samples. Collectively, our results demonstrate that loss of BOP1 and the resulting activation of the MAPK pathway is a clinically relevant mechanism for acquired resistance to BRAFi in melanoma.

KEYWORDS:

BOP1; BRAF inhibitor; RNAi; drug resistance; melanoma

PMID:
30782837
PMCID:
PMC6410847
[Available on 2019-09-05]
DOI:
10.1073/pnas.1821889116

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