Oncogenic mutations within the β3-αC loop of EGFR/ERBB2/BRAF/MAP2K1 predict response to therapies.

Background: beta 3-alpha C loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within beta 3-alpha C loop in EGFR, but relatively less in ERBB2, BRAE, and MAP2K1. In addition, previous studies mainly focus on beta 3-alpha C deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. Methods: Here we analyzed the profile of beta 3-alpha C loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture-based next-generation sequencing. Results: We identified 1616 mutations within beta 3-alpha C loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAE, and MAP2KI. EGFR beta 3-alpha C deletions occurred at a high percentage of 96.7% and were all drug-relevant. We also detected rare EGER beta 3-alpha C insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 beta 3-alpha C deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAE and MAP2K1 mutations within beta 3-alpha C loop also demonstrated drugs relevance. Conclusion: Our study showed that oncogenic mutations within the beta 3-alpha C loop of ERBB2, MAP2K1, and BRAE are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the beta 3-alpha C loop is critical for targeted therapies.