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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2
Scott A Foster1, Daniel M Whalen2, Ayşegül Özen3
1Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Abstract:
Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.
Insights
Oncogenic deletions in protein kinases like BRAF, HER2, and EGFR can activate cancer growth. These deletions, particularly five amino acids long, confer resistance to targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Structural Biology
Background:
- Activating mutations in protein kinases are key drivers of cancer.
- The impact of in-frame deletions on kinase activity remains poorly understood compared to point mutations.
Purpose of the Study:
- To investigate the functional and structural consequences of in-frame deletions in the β3-αC loop of HER2 and BRAF kinases.
- To understand the prevalence and implications of specific deletion lengths in oncogenic kinases.
Main Methods:
- Comparative analysis of oncogenic deletions in HER2, BRAF, and EGFR.
- Identification of BRAF deletions in pancreatic carcinomas.
- X-ray crystallography to determine the structure of BRAF deletions.
- Assessment of inhibitor resistance in mutated kinases.
Main Results:
- Oncogenic deletions in the β3-αC loop of HER2 and BRAF are analogous to EGFR exon 19 deletions.
- BRAF deletions were found to be mutually exclusive with KRAS mutations in pancreatic cancers.
- Crystal structures revealed that truncated loops lock the αC helix in an active conformation, conferring resistance to inhibitors like vemurafenib.
- The study explains the prevalence of five-amino acid deletions across BRAF, EGFR, and HER2.
Conclusions:
- In-frame deletions in the β3-αC loop are a significant mechanism of oncogenic kinase activation.
- The structural changes induced by these deletions lead to drug resistance.
- Understanding loop length is critical for kinase activity and the efficacy of targeted therapies.
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