Data from Simultaneous targeting of DNA polymerase theta and PARP1 or RAD52 triggers dual synthetic lethality in homologous recombination-deficient leukemia cells

Abstract

<div>Abstract<p>DNA polymerase theta (Polθ, encoded by <i>POLQ</i> 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 <i>Polq<sup>−/−</sup>;Parp1<sup>−/−</sup></i> and <i>Polq<sup>−/−</sup>;Rad52<sup>−/−</sup></i> 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.</p>Implications:<p>In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.</p></div>