Olaparib-Induced Mitochondrial Metabolic Collapse Promotes Apoptotic Priming and Overcomes Therapeutic Resistance in CLL

Abstract

Sonu Kumar*, Sourabh Kosey, Nanak Singh Toor and Khadga Raj Aran

Chronic lymphocytic leukemia (CLL) is a persistent CD5+ B-cell malignancy characterized by clonal expansion of mature B lymphocytes and sustained reliance on prosurvival and mitochondrial metabolic programs. Although Bruton tyrosine kinase inhibitors (BTKI) and BCL2 inhibitors (BCL2i), including ibrutinib and venetoclax, have redefined first- line therapy, CLL remains incurable, with relapse driven by both genomic lesions (e.g., BTK, PLCG2, BCL2 mutations, del(8p), gain2p, amp1q) and non-canonical resistance mechanisms such as oxidative phosphorylation (OXPHOS) re- modelling and altered BCL2–mitochondrial binding dynamics. Ayoub et al., demonstrate that olaparib, a clinically approved PARP inhibitor, sensitizes CLL cells to BTKI and BCL2i through a PARP1-independent mechanism rooted in mitochondrial metabolic collapse rather than DNA damage signalling [1]. Multi-layered bioenergetic profiling revealed profound suppression of mitochondrial oxygen consumption rate (OCR), ATP depletion, impaired TCA cycle flux, and destabilization of electron transport chain (ETC) complexes, collectively driving metabolic collapse, redox disequilibrium, and excess mitochondrial ROS (mtROS) accumulation. These mitochondrial injuries induced mitochondrial membrane depolarization and apoptotic priming, lowering the threshold for BCL2-mediated cell death. Genetic silencing of PARP1 failed to rescue drug sensitization, excluding classical PARP-dependent DNA repair or transcriptional effects. Pathway-network analyses further identified disrupted BTK/BCL2–mitochondrial crosstalk and weakened anti-apoptotic buffering, exposing ametabolic–survival co-dependency axis essential for leukemic persistence

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