Recent genome scale characterization of cancers identified overwhelming numbers of novel, rare and uncharacterized somatic mutations, variance of unknown significance (VUS), in non-small cell lung cancer (NSCLC). In order to make these VUS data clinically useful, further functional and biological characterization of each mutation is mandatory. In addition, development of novel strategies to overcome mutation diversity of lung cancer is needed.
Using the large-scale prospective cohort data of the LC-SCRUM-Japan, nationwide lung cancer clinical and the genomic characterization network in Japan, we characterized the frequency and distribution of rare EGFR mutations in NSCLC and the clinical course of the patients harboring these mutations. In addition, to perform functional and biological characterization of each mutation, we created a Ba/F3 EGFR minor mutation library. Furthermore, the in silico sensitivity prediction model has been developed to demonstrate binding affinity of protein and drug compound and applied to EGFR tyrosine kinase inhibitor with mutated EGFR.
Of the 2164 NSCLC patients examined by LC-SCRUM-Japan, 113 (5.2%) harbored rare EGFR mutations. We found the diverse distribution of EGFR mutations throughout the gene, the most frequent group included EGFR exon 20 insertion mutations (52 cases). We clarified the sensitivity profile of the VUS to EGFR tyrosine kinase inhibitors. Binding affinities calculated by the in silico sensitivity prediction model showed statistically significant correlation (R2: 0.7425, p < 0.05) with the experimentally observed IC50 values.
These data may help in choosing or predicting the appropriate inhibitor for lung cancer with VUS in EGFR, thereby contributing to the further development of precision medicine. Here, we clarified the diversity of VUS in EGFR and provide novel insights, via supercomputer utilized drug sensitivity prediction, in the cancer field.
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Keio University School of Medicine.
Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
All authors have declared no conflicts of interest.