Jacqulyne P. Robichaux, Xiuning Le, R. S. K. Vijayan, J. Kevin Hicks, Simon Heeke, Yasir Y. Elamin, Heather Y. Lin, Hibiki Udagawa, Ferdinandos Skoulidis, Hai Tran, Susan Varghese, Junqin He, Fahao Zhang, Monique B. Nilsson, Lemei Hu, Alissa Poteete, Waree Rinsurongkawong, Xiaoshan Zhang, Chenghui Ren, Xiaoke Liu, Lingzhi Hong, Jianjun Zhang, Lixia Diao, Russell Madison, Alexa B. Schrock, Jennifer Saam, Victoria Raymond, Bingliang Fang, Jing Wang, Min Jin Ha, Jason B. Cross, Jhanelle E. Gray & John V. Heymach
Nature (2021).
https://doi.org/10.1038/s41586-021-03898-1
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1,2,3. Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations4,5,6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7,8,9,10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
