PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

by Selleckchem | Aug 26 2023

Targeted therapies such as venetoclax (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple anti-apoptotic proteins and display resistance to pro-apoptotic agents. Here, we demonstrated that multidrug resistant CLL cells in vivo exhibit apoptosis restriction at a premitochondrial level due to insufficient activation of the Bax and Bak proteins. Co-immunoprecipitation analyses with selective BH-domain antagonists revealed that the pleotropic pro-apoptotic protein (Bim) is prevented from activating Bax/Bak by "switching" interactions to other upregulated anti-apoptotic proteins (Mcl-1/Bcl-xL/Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein Phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that a small molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug resistant leukemia/lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug resistant CLL cells through induction of mitochondrial permeability transition pores (mPTP), independent of Bax/Bak. DT-061 inhibited the growth of wild type and Bax/Bak double knockout multidrug resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug resistant CLL cells in patients, and validated a pharmacologically tractable pathway to deplete this reservoir.

Comments:

The passage describes a study focused on understanding and addressing the resistance of chronic lymphocytic leukemia (CLL) cells to targeted therapy, specifically the Bcl-2 inhibitor venetoclax. The researchers found that resistant CLL cells overexpress multiple anti-apoptotic proteins, which prevent the activation of pro-apoptotic proteins Bax and Bak. This restriction at a premitochondrial level leads to resistance to apoptosis-inducing agents.

The study further demonstrated that the pro-apoptotic protein Bim is prevented from activating Bax and Bak due to its interactions with other upregulated anti-apoptotic proteins such as Mcl-1, Bcl-xL, and Bcl-2. Therefore, the researchers concluded that treatments bypassing the Bax/Bak restriction are necessary to eliminate these resistant cells in CLL patients.

To address this challenge, the researchers investigated the role of Protein Phosphatase 2A (PP2A) in oncogenesis and treatment resistance. They discovered that a small molecule activator of PP2A called SMAP (DT-061) induced cytotoxicity in various cancer cell lines, including multidrug-resistant leukemia/lymphoma cells and CLL samples. DT-061 triggered apoptosis in multidrug-resistant CLL cells by inducing mitochondrial permeability transition pores (mPTP) independently of Bax/Bak. Importantly, DT-061 also inhibited the growth of multidrug-resistant CLL cells in a xenograft mouse model, including both wild type and Bax/Bak double knockout cells.

Overall, this study identified a population of multidrug-resistant CLL cells in patients and validated a promising approach to deplete these cells using a pharmacologically tractable pathway, namely the activation of PP2A with the SMAP DT-061. This research provides insights into potential strategies for overcoming resistance to targeted therapies in CLL and highlights the importance of understanding the molecular mechanisms underlying treatment resistance in cancer.