Author:
Ikemura Shinnosuke,Yasuda Hiroyuki,Matsumoto Shingo,Kamada Mayumi,Hamamoto Junko,Masuzawa Keita,Kobayashi Keigo,Manabe Tadashi,Arai Daisuke,Nakachi Ichiro,Kawada Ichiro,Ishioka Kota,Nakamura Morio,Namkoong Ho,Naoki Katsuhiko,Ono Fumie,Araki Mitsugu,Kanada Ryo,Ma Biao,Hayashi Yuichiro,Mimaki Sachiyo,Yoh Kiyotaka,Kobayashi Susumu S.,Kohno Takashi,Okuno Yasushi,Goto Koichi,Tsuchihara Katsuya,Soejima Kenzo
Abstract
Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance ofEGFRmutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspotEGFRmutations (n= 3,779) revealed that the majority (>90%) of cases with rareEGFRmutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2= 0.72,P= 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rareEGFRmutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.
Funder
MEXT | Japan Society for the Promotion of Science
MEXT | RIKEN | Advanced Science Institute
Japan Agency for Medical Research and Development
HHS | National Institutes of Health
DOD | United States Army | MEDCOM | Congressionally Directed Medical Research Programs
Publisher
Proceedings of the National Academy of Sciences