Targeting homologous recombination repair in BCR/ABL1-positive cells using PARP inhibitors
BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit the growth of CML and Ph1-ALL cells with downregulated BRCA1 expression. Inhibition of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. Here, we demonstrate that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. Inhibition of leukemogenesis in BCR/ABL1-positive cells was the result of a combination of the direct cytotoxic effects of olaparib and reduced maintenance of BCR/ABL1-positive stem cells. Interferon was used as a first-line therapy for CML. Activation of the cGAS/STING pathway was also observed upon PARP inhibition. However, fully transformed BCR/ABL1-positive leukemic cell lines showed a variable response to olaparib, presumably due to cancer-associated genetic alterations other than BCR/ABL1. To overcome this, we manipulated the phosphatidylinositol 3-kinase (PI3K) pathway involved in PARP resistance using a PI3K inhibitor. This increased olaparib cytotoxicity in BCR/ABL1-positive leukemic cell lines. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, PARPi could be combined with TKIs or a PI3K inhibitor to induce CML or Ph1-ALL cell death more effectively.