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

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Nikolay V. Pervushin^1,2, Bertha Y. Valdez Fernandez², Vyacheslav V. Senichkin², Maria A. Yapryntseva^1,2, Vladislav S. Pavlov¹, Boris Zhivotovsky^1,2,3,a*, and Gelina S. Kopeina^1,2,b*

¹Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

²Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia

³Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden

^* To whom correspondence should be addressed.

Received: August 24, 2025; Revised: October 22, 2025; Accepted: October 29, 2025

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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.

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KEY WORDS: drug resistance, Mcl-1, BH3 mimetics, apoptosis, cancer cells

DOI: 10.1134/S0006297925602710

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