Supplementary Figure 3 from Simultaneous targeting of DNA polymerase theta and PARP1 or RAD52 triggers dual synthetic lethality in homologous recombination-deficient leukemia cells

Sullivan-Reed, Katherine; Toma, Monika M.; Drzewiecka, Malgorzata; Nieborowska-Skorska, Margaret; Nejati, Reza; Karami, Adam; Wasik, Mariusz A.; Sliwinski, Tomasz; Skorski, Tomasz

doi:10.1158/1541-7786.27035161.v1

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Supplementary Figure 3 from Simultaneous targeting of DNA polymerase theta and PARP1 or RAD52 triggers dual synthetic lethality in homologous recombination-deficient leukemia cells

journal contribution

posted on 2024-09-16, 11:47 authored by Katherine Sullivan-Reed, Monika M. Toma, Malgorzata Drzewiecka, Margaret Nieborowska-Skorska, Reza Nejati, Adam Karami, Mariusz A. Wasik, Tomasz Sliwinski, Tomasz Skorski

S3. Simultaneous inhibition of Polθ helicase and DNA polymerase activity exerted synergistic effect against RAD54-/- leukemia cells.

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ARTICLE ABSTRACT

DNA polymerase theta (Poltheta, encoded by POLQ gene) plays an essential role in Poltheta-mediated end-joining (TMEJ) of DNA double-strand breaks (DSBs). 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. Since leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Pol 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 to 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.