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

BACKGROUND: β3‐αC 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 β3‐αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3‐αC 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 β3‐αC 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 β3‐αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3‐αC deletions occurred at a high percentage of 96.7% and were all drug‐relevant. We also detected rare EGFR β3‐αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3‐αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3‐αC loop also demonstrated drugs relevance. CONCLUSION: Our study showed that oncogenic mutations within the β3‐αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3‐αC loop is critical for targeted therapies.