2. Academic Validation
  3. Bemcentinib enhances sensitivity to estrogen receptor inhibitors in breast cancer cells

Bemcentinib enhances sensitivity to estrogen receptor inhibitors in breast cancer cells

  • Int J Biochem Cell Biol. 2025 Feb 1:180:106750. doi: 10.1016/j.biocel.2025.106750.
Gyeongmi Kim 1,  Se Hee Ahn 2,  Se-Kyeong Jang 3,  Selim Kim 1,  Hyunggee Kim 4,  Ki Soo Park 5,  Hyeon-Ok Jin 6,  Chan Sub Park 7,  Min-Ki Seong 7,  Hyun-Ah Kim 8,  In-Chul Park 9
Affiliations

Affiliations

  • 1 Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 2 Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea; Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea.
  • 3 Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 4 Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 5 Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea.
  • 6 KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 7 Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 8 Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: hyunah@kirams.re.kr.
  • 9 Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: parkic@kirams.re.kr.
PMID: 39900236 DOI: 10.1016/j.biocel.2025.106750
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.

Keywords

Bemcentinib; Estrogen receptor-positive breast cancer; S6K1; STAT3; Tamoxifen resistance.

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