Bemcentinib enhances sensitivity to estrogen receptor inhibitors in breast cancer cells

Abstract

Estrogen receptor (ER)-positive breast cancer accounts for a substantial proportion of breast cancer cases and is typically managed using ER inhibitors, such as tamoxifen and fulvestrant. However, the development of resistance to these therapies is a significant clinical challenge, and the improvement of therapeutic strategies is crucial. This study aimed to investigate the potential of bemcentinib, a well-known AXL inhibitor, to enhance the sensitivity of MCF7 breast cancer cells to 4-hydroxytamoxifen (4-OHT) and fulvestrant. Our findings revealed that bemcentinib effectively decreased S6K1 phosphorylation and synergistically induced cell death when used in combination with ER inhibitors. Bemcentinib treatment also unexpectedly activated STAT3, and inhibition of STAT3 enhanced cell death induced by bemcentinib and 4-OHT. Notably, the combination of bemcentinib and 4-OHT effectively induced cell death even in tamoxifen-resistant MCF7 cells (MCF7-TR), highlighting its potential to overcome tamoxifen resistance. Interestingly, AXL knockdown did not enhance the sensitivity to 4-OHT or affect S6K1 signaling in either MCF7 or MCF7-TR cells, suggesting that the sensitizing effect of bemcentinib through S6K1 inhibition may be independent of AXL expression. Our findings suggest that bemcentinib treatment, particularly in combination therapy, could be a promising strategy for improving treatment efficacy and overcoming tamoxifen resistance in ER-positive breast cancer.