THE MECHANISMS AND PATHWAYS TO OVERCOME THE ACQUIRED RESISTANCE OF TUMOR CELLS TO Mcl-1 ANTAGONISTS

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Abstract

Acquired drug resistance reduces the efficiency of cancer treatment and leads to cancer progression. The selective inhibition of antiapoptotic proteins from the Bcl-2 family by BH3 mimetics is a promising strategy for the treatment of cancer patients. In recent years, antagonists of the antiapoptotic protein Mcl-1 have been intensively studied in clinical trials; however, like other BH3 mimetics, they may lose their effectiveness due to the development of acquired resistance. We have found that tumor cells develop resistance to Mcl-1 inhibition due to increased expression of genes of other antiapoptotic proteins (Bcl-2 or Bcl-xL), becoming less Mcl-1-dependent. The development of this type of resistance can also be accompanied by changes in cell metabolism. We have shown that combining Mcl-1 antagonist S63845 and various antitumor compounds can lead to overcoming the resistance of malignant cells to its action.

About the authors

N. V. Pervushin

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Faculty of Basic Medicine, Lomonosov Moscow State University

Email: lirroster@gmail.com
Moscow, Russia; Moscow, Russia

B. Y. Valdez Fernandez

Faculty of Basic Medicine, Lomonosov Moscow State University

Moscow, Russia

V. V. Senichkin

Faculty of Basic Medicine, Lomonosov Moscow State University

Moscow, Russia

M. A. Yapryntseva

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Faculty of Basic Medicine, Lomonosov Moscow State University

Moscow, Russia; Moscow, Russia

V. S. Pavlov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Moscow, Russia

B. Zhivotovsky

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Faculty of Basic Medicine, Lomonosov Moscow State University; Institute of Environmental Medicine, Karolinska Institute

Email: boris.zhivotovsky@ki.se
Moscow, Russia; Moscow, Russia; Stockholm, Sweden

G. S. Kopeina

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Faculty of Basic Medicine, Lomonosov Moscow State University

Moscow, Russia; Moscow, Russia

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