| First Author | Sullivan-Reed K | Year | 2023 |
| Journal | Mol Cancer Res | Volume | 21 |
| Issue | 10 | Pages | 1017-1022 |
| PubMed ID | 37358557 | Mgi Jnum | J:342484 |
| Mgi Id | MGI:7545489 | Doi | 10.1158/1541-7786.MCR-22-1035 |
| Citation | Sullivan-Reed K, et al. (2023) Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination-Deficient Leukemia Cells. Mol Cancer Res 21(10):1017-1022 |
| abstractText | DNA polymerase theta (Poltheta, encoded by POLQ gene) plays an essential role in Poltheta-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Poltheta 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 Poltheta 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 Poltheta (Polthetai) 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. IMPLICATIONS: In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polthetai against HR-deficient leukemias. |
