부산대학교 도서관

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the [EGFR.sup.T790M] gatekeeper mutation can occur either by selection of pre- existing [EGFR.sup.T790M]-positive clones or via genetic evolution of initially [EGFR.sup.T790M]-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target [EGFR.sup.T790M]; treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor- resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
Despite the success of targeted cancer therapies, the duration of clinical response is limited by the inevitable development of acquired drug resistance, as in the case of EGFR-mutated non-small-cell lung [...]