Drug-resistant EGFRT790M mutations can preexist or be acquired de novo during drug treatment.
Major finding: Drug-resistant EGFRT790M mutations can preexist or be acquired de novo during drug treatment.
Concept: The path to resistance influences the biology of the resistant cells and the response to treatment.
Impact: Treatment with third-generation EGFR inhibitors and navitoclax may be effective in EGFRT790M tumors.
Non–small cell lung cancers (NSCLC) often respond well to EGFR inhibitors initially, but eventually develop drug resistance. However, the mechanisms by which resistant clones arise during drug therapy are not well understood. To better understand the processes underlying resistance, Hata, Niederst, and colleagues used EGFR-mutant NSCLC cells grown in the presence of the EGFR inhibitor gefitinib until EGFRT790M resistant clones emerged. Clones that developed early resistance were more sensitive to treatment with the third-generation EGFR inhibitor WZ4002 than cells that developed late resistance both in vitro and in vivo. All early-resistant colonies contained the EGFRT790M mutation. Using a high-complexity DNA barcode library to track the evolution of resistant clones, the authors showed that these early-resistant clones arose from rare preexisting EGFRT790M-mutant cells that were selected for with gefitinib treatment. In contrast, late-resistant cells emerged from EGFRT790M negative cells after prolonged culture in gefitinib and acquired EGFRT790M or other putative resistance mutations, suggesting that de novo EGFRT790M mutations occurred in drug-tolerant cells during treatment. This idea was further supported by transcriptional profiles, which indicated that late-resistant cells were most similar to drug-tolerant EGFRT790M-negative cells, suggesting that even after acquiring the EGFRT790M mutation, late-resistant cells maintained molecular features of the drug-tolerant state. Furthermore, WZ4002 induced a less robust apoptotic response in late-resistant EGFRT790M cells compared with early-resistant clones, and combined treatment with the dual BCLXL/BCL2 inhibitor navitoclax improved the apoptotic activity of third-generation EGFR inhibitors in patient-derived EGFR-mutant NSCLC samples. Thus, EGFRT790M mutations leading to drug resistance can arise de novo, or be selected for from preexisting cells, and the path to resistance influences the response to subsequent EGFR inhibitor treatment. These findings also suggest that dual treatment with navitoclax and third-generation EGFR inhibitors may be more effective in overcoming resistance to EGFR inhibitors.
Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 2016 Feb 1 [Epub ahead of print].
- ©2016 American Association for Cancer Research.