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

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.