The ClpP activator ONC-212 (TR-31) inhibits BCL2 and B-cell receptor signaling in CLL

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Chronic lymphocytic leukemia (CLL) often relapses with drug-resistant disease, necessitating novel therapeutic strategies.
• High-risk CLL patients particularly require innovative treatment approaches.
• Imipridones are a new class of anti-cancer agents with demonstrated efficacy in various cancers.

Purpose of the Study:

• To investigate the anti-leukemic effects of the imipridone ONC-212 on chronic lymphocytic leukemia (CLL) cells.
• To evaluate ONC-212's efficacy in a TP53-deficient CLL cell line and under conditions mimicking the tumor microenvironment.
• To elucidate the molecular mechanisms underlying ONC-212's action in CLL.

Main Methods:

• Culturing CLL cells under specific conditions, including a TP53-knockout (TP53ko) cell line.
• Treating CLL cells with the imipridone ONC-212.
• Assessing apoptosis, cell cycle arrest, and migration.
• Analyzing protein expression changes related to mitochondrial pathways, stress responses, B-cell receptor (BCR) signaling, and BCL2 family proteins.

Main Results:

• ONC-212 induced dose-dependent apoptosis, cell cycle arrest, and reduced migration in CLL cells, including TP53-mutated and TP53ko cells.
• Treatment with ONC-212 activated the mitochondrial protease CIpP and the integrated stress response.
• ONC-212 inhibited downstream BCR signaling pathways (AKT, MAPK-ERK1/2) and modulated BCL2 family protein expression, favoring apoptosis.

Conclusions:

• ONC-212 demonstrates significant anti-leukemic activity against CLL cells in vitro.
• The drug's mechanism involves inhibiting BCR signaling and promoting apoptosis through BCL2 family protein modulation.
• ONC-212 shows potential as an effective treatment for high-risk and drug-resistant CLL.