Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
Mol Cancer Res. 2023 Oct 2;21(10):1017-1022. doi: 10.1158/1541-7786.MCR-22-1035.
DNA polymerase theta (Polθ, encoded by POLQ gene) plays an essential role in Polθ-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Polθ is synthetic lethal in homologous recombination (HR)-deficient tumor cells. However, DSBs can be also repaired by PARP1 and RAD52-mediated mechanisms. Because leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Polθ and PARP1 or RAD52 enhance the synthetic lethal effect in HR-deficient leukemia cells. Transformation potential of the oncogenes inducing BRCA1/2-deficiency (BCR-ABL1 and AML1-ETO) was severely limited in Polq-/-;Parp1-/- and Polq-/-;Rad52-/- cells when compared with single knockouts, which was associated with accumulation of DSBs. Small-molecule inhibitor of Polθ (Polθi) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells.
In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.
DNA 聚合酶 θ（Polθ，由 POLQ 基因编码）在 Polθ 介导的 DNA 双链断裂（DSB）末端连接（TMEJ）中发挥重要作用。Polθ 的抑制在同源重组（HR）缺陷型肿瘤细胞中是合成致死的。然而，DSB 也可以通过 PARP1 和 RAD52 介导的机制进行修复。由于白血病细胞会积累自发的 DSB，我们测试了同时靶向 Polθ 和 PARP1 或 RAD52 是否会增强 HR 缺陷型白血病细胞中的合成致死效应。与单敲除相比，BRCA1/2 缺陷（BCR-ABL1 和 AML1-ETO）诱导的致癌基因的转化潜力在 Polq-/-；Parp1-/-和 Polq-/-；Rad52-/-细胞中受到严重限制，这与 DSB 的积累有关。Polθ 的小分子抑制剂（Polθi）与 PARP 或 RAD52 抑制剂（PARPi、RAD52i）联合使用会导致 DSB 的积累，并对 HR 缺陷型白血病和骨髓增生性肿瘤细胞产生更大的作用。
总之，我们表明，PARPi 或 RAD52i 可能会提高 Polθi 对 HR 缺陷型白血病的治疗效果。
