Synergistic effect of combined PI3 kinase inhibitor and PARP inhibitor treatment on BCR/ABL1-positive acute lymphoblastic leukemia cells.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) function by inhibiting base excision repair and inducing synthetic lethality in homologous recombination repair-deficient cells, such as BRCA1/2-mutated cancer cells. The BCR/ABL1 fusion protein causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). BCR/ABL1 also induces genomic instability by downregulating BRCA1. We investigated the effect of the PARPi, olaparib, against Ph+ALL cell lines and found that they show variable sensitivity, presumably due to cancer-associated genetic alterations other than BCR/ABL1. To investigate the reasons for the variable responses of Ph+ALL cells to PARPi treatment, we analyzed the transcriptomes of olaparib-sensitive and -resistant Ph+ALL cell lines, which revealed that activation of the phosphatidylinositol 3-kinase (PI3K) pathway was a hallmark of PARPi resistance. Based on these findings, we examined the effects of adding a PI3K inhibitor (PI3Ki) to PARPi treatment to overcome PARPi insensitivity in Ph+ALL cell lines. Combination with PI3Ki increased PARPi cytotoxicity in PARPi-resistant Ph+ALL cell lines. Tyrosine kinase inhibitor (TKI) therapy is the gold standard for Ph+ALL, and, based on our findings, we propose that PARPi combined with TKI and PI3K inhibition could be a novel therapeutic strategy for Ph+ALL.