Supplementary Figure 4 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:10.1158/1541-7786.24229695.v1

Supplementary Figure 4 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 2023-10-02, 07:43 authored by Katherine Sullivan-Reed, Monika M. Toma, Malgorzata Drzewiecka, Margaret Nieborowska-Skorska, Reza Nejati, Adam Karami, Mariusz A. Wasik, Tomasz Sliwinski, Tomasz Skorski

S4. Targeting Polθ + PARP and Polθ + RAD52 induced dual synthetic lethality against HR -deficient MPN cells.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

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.