期刊
CLINICAL CANCER RESEARCH
卷 25, 期 11, 页码 3341-3351出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3829
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资金
- NIH [S10 OD020154, R01GM080403, R01GM099842, R01GM073151]
- NCI [R01CA121210, P01CA129243, P30CA68485]
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- V Foundation Scholar-in-Training Award
- Lung Cancer Foundation of America/International Association for the Study of Lung Cancer Lori Monroe Scholarship
- NIH by a Ruth L. Kirschstein NRSA fellowship [F30DK118774]
- Ruth L. Kirschstein NRSA Fellowship [T32HL094296]
Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective thirdgeneration inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. Results: Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. Conclusions: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the drug-resistance mutation pair to one focused on the activating mutation-drug-resistance mutation trio. This has broad implications across clinical oncology.
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