Reversible Drug Resistance Mechanisms in Non-small Cell Lung Cancer

Abstract

Although molecular targeted drugs are significantly effective in many types of cancer treatment, almost all patients suffer from drug resistance. For instance, non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation invariably develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and melanoma patients with BRAF mutation develop resistance to BRAF inhibitors. Mechanistically, genetic and irreversible resistance mechanisms have been studied for more than a decade, while non-mutational and reversible resistance mechanisms are yet to be clearly understood. Since drug tolerant persisters (DTPs), which emerge at the beginning of the drug treatment, have been reported in 2010, several non-mutational tolerance mechanisms have been reported by various researchers. Furthermore, with the advancement in single cell sequencing technology, increasing attention has been drawn towards the investigation of the heterogeneous characteristics of drug tolerant cell populations. Here, we describe the recent advances in non-mutational drug tolerant mechanisms toward the molecular targeted drugs. In our study, we tried to elucidate the unconventional resistance mechanisms by utilizing newly approved EGFR-TKI, dacomitinib. Our established drug resistant cells did not gain new mutation in EGFR even after long time exposure to the drug. In addition, the drug resistance vanished when resistant cells were implanted in mice, which indicates that mechanisms conferring drug sensitivity might be host-dependent. Thus, our study may provide a new insight into non-mutational drug tolerant mechanisms.