Although most EGFR-mutant lung adenocarcinomas initially respond to EGFR inhibitors, disease progression almost inevitably occurs. We previously reported that two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, contain subpopulations of cells that display an epithelial-to-mesenchymal phenotype and can thrive independently of EGFR signaling. In this study, we explored to what extent these two sublines, HCC827 GR2 and H1975 WR7, depended on the anti-apoptotic BCL2 family members, Bcl-xL and/or MCL1, for survival. Although HCC827 GR2 cells were hardly affected by Bcl-xL or MCL1 knockdown alone, dual inhibition of Bcl-xL and MCL1 caused the cells to undergo apoptosis, resulting in decreased viability. In H1975 WR7 cells, not only dual inhibition, but also MCL1 silencing alone, induced the cells to undergo apoptosis. Interestingly, the two sublines markedly declined in number when autophagy flux was suppressed, because they depend, in part, on active autophagy for survival. However, autophagy inhibition was inferior to dual inhibition of Bcl-xL plus MCL1 for GR2 cells, or MCL1 inhibition alone, for decreasing the viability of WR7 cells. Collectively, these findings suggest that inhibiting Bcl-xL plus MCL1, or MCL1 alone, may represent a new approach to treat EGFR-independent EGFR-mutant cancer cells.
Keywords: Autophagy; Bcl-xL; EGFR-mutant lung adenocarcinoma; Epithelial-to-mesenchymal transition (EMT); MCL1.
Copyright © 2020 Elsevier Inc. All rights reserved.