2. Academic Validation
  3. A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor

A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor

  • Cancer Discov. 2018 Sep;8(9):1130-1141. doi: 10.1158/2159-8290.CD-17-1263.
Jiawan Wang 1,  Zhan Yao 2,  Philip Jonsson 3 4,  Amy N Allen 1,  Alice Can Ran Qin 1,  Sharmeen Uddin 2,  Ira J Dunkel 5 6,  Mary Petriccione 5,  Katia Manova 7,  Sofia Haque 8,  Marc K Rosenblum 9,  David J Pisapia 10,  Neal Rosen 2,  Barry S Taylor 3 4 11,  Christine A Pratilas 12
Affiliations

Affiliations

  • 1 Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 4 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 5 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 6 Department of Pediatrics, Weill Cornell Medical College, New York, New York.
  • 7 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 8 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 9 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 10 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
  • 11 Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 12 Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. cpratil1@jhmi.edu.
PMID: 29880583 DOI: 10.1158/2159-8290.CD-17-1263
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. Cancer Discov; 8(9); 1130-41. ©2018 AACR.See related commentary by Romano and Kwong, p. 1064This article is highlighted in the In This Issue feature, p. 1047.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18972
    99.94%, BRAF Inhibitor
    Raf