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Abstract <p>Acquired drug resistance reduces the effectiveness of anticancer therapy and leads to cancer progression. Selective inhibition of anti-apoptotic proteins of the Bcl-2 family using BH3-mimetics is a promising treatment strategy for cancer patients. Recently, antagonists of the anti-apoptotic protein Mcl-1 have been actively studied in clinical trials. However, like other BH3-mimetics, they can lose their effectiveness due to the development of acquired resistance. We have found that cancer cells develop resistance to Mcl-1 inhibition through increased gene expression of other anti-apoptotic proteins, such as Bcl-2 or Bcl-xL, thereby becoming less Mcl-1-dependent. Alterations in cellular metabolism have also accompanied the development of this resistance. We have shown that combining the Mcl-1 antagonist S63845 with various anticancer compounds can overcome the resistance of malignant cells to its action.</p>

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Mechanisms and Ways to Overcome Acquired Resistance of Cancer Cells to Mcl-1 Antagonists

  • 期刊论文

  • 发表日期：

    2025年12月23日

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  • Nikolay V. Pervushin,
  • Bertha Y. Valdez Fernandez,
  • Vyacheslav V. Senichkin,
  • Maria A. Yapryntseva,
  • Vladislav S. Pavlov,
  • Boris Zhivotovsky,
  • Gelina S. Kopeina

摘要

Abstract

Acquired drug resistance reduces the effectiveness of anticancer therapy and leads to cancer progression. Selective inhibition of anti-apoptotic proteins of the Bcl-2 family using BH3-mimetics is a promising treatment strategy for cancer patients. Recently, antagonists of the anti-apoptotic protein Mcl-1 have been actively studied in clinical trials. However, like other BH3-mimetics, they can lose their effectiveness due to the development of acquired resistance. We have found that cancer cells develop resistance to Mcl-1 inhibition through increased gene expression of other anti-apoptotic proteins, such as Bcl-2 or Bcl-xL, thereby becoming less Mcl-1-dependent. Alterations in cellular metabolism have also accompanied the development of this resistance. We have shown that combining the Mcl-1 antagonist S63845 with various anticancer compounds can overcome the resistance of malignant cells to its action.