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Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Published version of a preprint
Abstract
We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490–deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer–dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive. Significance: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. Cancer Discov; 6(3); 300–15. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 217
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“It is known that in contrast to melanoma, cases of KRAS wild type PDAC, including the BxPC3 cell line itself, acquire in-frame deletions of BRAF that result in constitutive activation of the kinase domain (Chen 2016)15.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as Chen 2016)15
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Metadata
- Authors
- Chen, S.-H., Zhang, Y., Van Horn, R. D., Yin, T., Buchanan, S., Yadav, V., Mochalkin, I., Wong, S. S., Yue, Y. G., Huber, L., Conti, I., Henry, J. R., Starling, J. J., Plowman, G. D., & Peng, S.-B.
- Affiliations
- Eli Lilly (United States) (US)
- 1Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
- Corresponding author
- Peng, Sheng-Bin
- ORCID
- Venue
- Cancer Discovery
- Published
- 2016-03-01
- Volume
- 6
- Issue
- 3
- Pages
- 300-315
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2309935793
- Cited by
- 171
- References
- 47
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 24 · 2023: 22 · 2022: 23 · 2021: 15 · 2020: 13 · 2019: 16 · 2018: 17 · 2017: 19 · 2016: 5
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- LY3009120, vemurafenib resistance, αC-helix, MAPK signaling, KRAS wild-type pancreatic cancer, proximity ligation assay
- MeSH terms
- Ectopic Gene Expression, Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Disease Models, Animal, Humans, Models, Molecular, Phenylurea Compounds, Protein Conformation, Pyrimidines, Gene Expression, Gene Deletion, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Mice, Protein Interaction Domains and Motifs, Protein Multimerization
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