@article{f1492f7f3ea44b63af9d3b1f83bbb38e,
title = "A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAFV600E-mutant brain tumor",
abstract = "BRAFV600E hyperactivates ERK and signals as a RAF inhibitor–sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. SIGnIFICAnCE: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/ L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance.",
author = "Jiawan Wang and Zhan Yao and Philip Jonsson and Allen, {Amy N.} and Qin, {Alice Can Ran} and Sharmeen Uddin and Dunkel, {Ira J.} and Mary Petriccione and Katia Manova and Sofia Haque and Rosenblum, {Marc K.} and Pisapia, {David J.} and Neal Rosen and Taylor, {Barry S.} and Pratilas, {Christine A.}",
note = "Funding Information: We are grateful to the patient described and to his family who provided authorization for research; to the clinical investigators and Study Sponsor for the Novartis phase I/II trial of dabrafenib in pediatric patients (NCT01677741); to Lusong Luo and BeiGene for provision of compounds; and to Afsar Barlas and Gouri Nanjangud of the Molecular Cytology and Molecular Cytogenetics Core Facilities of MSKCC for assistance with pERK IHC and FISH studies, respectively. This work has been funded by the NIH: K08 CA127350 (to C.A. Pratilas), P30 CA008748, U54 OD020355 (to B.S. Taylor), R01 CA204749 (to B.S. Taylor); Giant Food Pediatric Cancer Fund (to C.A. Pratilas); Sontag Foundation (to B.S. Taylor); and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology of MSKCC. Funding Information: We are grateful to the patient described and to his family who provided authorization for research; to the clinical investigators and Study Sponsor for the Novartis phase I/II trial of dabrafenib in pediatric patients (NCT01677741); to Lusong Luo and BeiGene for provision of compounds; and to Afsar Barlas and Gouri Nanjangud of the Molecular Cytology and Molecular Cytogenetics Core Facilities of MSKCC for assistance with pERK IHC and FISH studies, respectively. This work has been funded by the NIH: K08 CA127350 (to C.A. Pratilas), P30 CA008748, U54 OD020355 (to B.S. Taylor), R01 CA204749 (to B.S. Taylor); Giant Food Pediatric Cancer Fund (to C.A. Pratilas); Sontag Foundation (to B.S. Taylor); and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology of MSKCC. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = sep,
doi = "10.1158/2159-8290.CD-17-1263",
language = "English (US)",
volume = "8",
pages = "1130--1141",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}