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
  • 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. [email protected].
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.

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