Mechanisms and Ways to Overcome Acquired Resistance of Cancer Cells to Mcl-1 Antagonists
Nikolay V Pervushin1,2, Bertha Y Valdez Fernandez2, Vyacheslav V Senichkin2
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
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.
Insights
Cancer cells can develop resistance to Mcl-1 inhibitors by increasing other anti-apoptotic proteins. Combining Mcl-1 antagonists with other anticancer drugs can overcome this acquired resistance, improving cancer therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Drug Resistance
Background:
- Acquired drug resistance is a major challenge in cancer therapy, leading to disease progression.
- BH3-mimetics targeting anti-apoptotic Bcl-2 family proteins offer a promising therapeutic strategy.
- Mcl-1 antagonists are under investigation but face acquired resistance, necessitating new treatment approaches.
Purpose of the Study:
- To investigate the mechanisms by which cancer cells acquire resistance to Mcl-1 inhibition.
- To explore strategies for overcoming Mcl-1 inhibitor resistance in cancer treatment.
Main Methods:
- Utilized cancer cell models to study acquired resistance to Mcl-1 inhibition.
- Analyzed gene expression changes, including other anti-apoptotic proteins (Bcl-2, Bcl-xL).
- Investigated metabolic alterations associated with resistance development.
- Evaluated the efficacy of combining Mcl-1 antagonist S63845 with other anticancer compounds.
Main Results:
- Cancer cells developed resistance to Mcl-1 inhibition by upregulating Bcl-2 or Bcl-xL expression.
- This upregulation reduced cellular dependence on Mcl-1.
- Acquired resistance was accompanied by significant alterations in cellular metabolism.
- Combination therapy with S63845 and other anticancer agents effectively overcame Mcl-1 inhibitor resistance.
Conclusions:
- Upregulation of Bcl-2 or Bcl-xL is a key mechanism of acquired resistance to Mcl-1 inhibitors.
- Metabolic reprogramming is linked to the development of this resistance.
- Combining Mcl-1 antagonists with other anticancer drugs is a viable strategy to overcome acquired resistance and enhance therapeutic outcomes in cancer.
Related Concept Videos
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:27Tumor Immunotherapy
02:38Mitogens and the Cell Cycle