Combining the cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib with the BCL-2 inhibitor venetoclax induced synergistic anti-tumor activity and efficacy against mantle cell lymphoma (MCL) in a relapsed or refractory (R/R) MCL animal model. The combination also showed a favorable safety profile in animals. These results were published in Blood Advances.1
“We discovered that the dual targeting of cell cycle and apoptosis regulators CDK4/6 and BCL-2 is a promising therapeutic strategy in treating aggressive R/R MCL,” said study author Vivian Changying Jiang, PhD, associate professor in the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston.
Both drugs tested as a combination are approved by the U.S. Food and Drug Administration to treat other cancer types. Abemaciclib is approved to treat breast cancer, including as a monotherapy to treat hormone receptor-positive metastatic breast cancer. Venetoclax is approved to treat patients with chronic lymphocytic leukemia or small lymphocytic lymphoma and in combination with other drugs as a treatment for patients with newly diagnosed acute myeloid leukemia.
A characteristic of MCL cells is the overexpression of the cyclin D1 protein, which results in faulty cell cycle progression and, in turn, results in an overabundance of complexes that include cyclin D1 and CDK 4/6. Thus, CDK 4/6 is a therapeutic target for MCL, although the CDK 4/6 inhibitor abemaciclib has been shown to have disappointing activity as monotherapy, with an overall response rate of about 35% in a phase II trial in patients with R/R MCL.2 The anti-programmed cell death protein BCL-2 is also often overexpressed in MCL cells. Because resistance to programmed cell death is often seen in cancer cells to promote their survival, the researchers reasoned that combining a CDK 4/6 inhibitor with a BCL-2 inhibitor may result in better efficacy in MCL than either drug alone. The team “discovered that the combination could exert a more robust anti-MCL activity than single agents,” said Dr. Jiang.
The team initially demonstrated that CDK 4/6 and cyclin D1 were constantly detectable in patient samples. They found that abemaciclib had potent activity against the MCL cell lines that did not harbor resistance to venetoclax but was not active against those MCL cell lines that were resistant to venetoclax.
Using primary patient cell lines, the team found that the abameciclib-venetoclax combination resulted in anti-tumor synergy compared to treatment with either drug alone. To understand the mechanism, the researchers analyzed the genes that were differently expressed in the cells that were treated with the combination compared to either drug alone. They found that the combination resulted in downregulation of the HSP27 protein compared to single-agent treatment. HSP27 is generally upregulated when cells are under stress and is known to protect cells against programmed cell death and other types of cell death, thus promoting tumor growth. When Dr. Jiang and her colleagues either overexpressed or knocked out HSP27, they found a crucial role of the protein in promoting MCL cell proliferation and resistance of the cells to therapy.
“HSP27 is a novel vulnerability for therapeutic development,” noted Dr. Jiang. “We are currently working to understand the exact role of HSP27 in mediating therapeutic resistance and to develop a potential therapy targeting HSP27.
“Our study provides a strong rationale for further preclinical evaluation of this combinatorial strategy, which can hopefully be translated into a clinical setting for the treatment of patients with R/R MCL.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Che Y, Liu Y, Li Y, et al. Dual targeting of CDK4/6 and Bcl-2 exhibits a potent antitumor effect on mantle cell lymphoma. Blood Advances. 2023;7(14):3361-3365.
- Morschhauser F, Bouabdallah K, Stilgenbauer S, et al. Clinical activity of abemaciclib in patients with relapsed or refractory mantle cell lymphoma - a phase II study. Haematologica. 2021;106(3):859-862.
