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Target Overview
Tumor cells with compromised DNA repair mechanisms (such as loss of BRCA1 or BRCA2 function, affecting double-strand break repair through homologous recombination), rely on the activity of alternative repair mechanisms for survival – an approach successfully exploited therapeutically using PARP inhibitors, which block single-strand break repair.1,2
An alternative DNA repair mechanism required for the survival of homologous recombination repair (HRR) defective cells is microhomology-mediated end joining (MMEJ), a pathway controlled by the activity of DNA polymerase theta (Polθ, POLQ).3,4 MMEJ repair is also responsible of causing secondary reversion mutations in HRR genes, the best-characterised mechanism of resistance to PARP inhibitors in the clinic.5,6
Inhibition of POLQ with AZD4956 leads to an increase in unrepaired DNA breaks caused by PARP inhibition, enhancing cancer cell death in tumors with HRR defects.7,8
Compound Overview
AZD4956 is an investigational inhibitor of POLQ. It is designed to selectively inhibit the DNA polymerase activity of POLQ to improve the efficacy of PARP inhibitors by increasing the accumulation of DNA damage and preventing the acquisition of PARP inhibitor resistance in tumors with HRR defects. Low expression of POLQ in normal tissue predicts minimal impact of AZD4956 on the toxicity profile of PARP inhibitor treatment.7,8
Mechanism of Action
References
1. Pommier Y, O’Connor MJ, De Bono J. Science translational medicine. 2016;8(362):362ps17. 2. Yap TA, Manning HC, Sapra P, Mills GB, O’Connor MJ. Cell. 2026;189(8):2278-306. 3. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. Nature. 2015;518(7538):258. 4. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. Nature. 2015;518(7538):254-257. 5. Pettitt SJ, Frankum JR, Punta M, Lise S, Alexander J, Chen Y, et al. Cancer discovery. 2020;10(10):1475-1488. 6. Tobalina L, Armenia J, Irving E, O'Connor MJ, Forment JV. Annals of Oncology. 2021;32(1):103-112. 7. Forment JV, Mulderrig L, de Renty C, Southgate H, Jones G, Gesu M, et al. Cancer Research. 2026;86(7_Supplement):230. 8. Barlaam B, Forment JV, Mulderrig L, Christelle DR, Southgate H, Hughes A, et al. Cancer Research. 2026;86(7_Supplement):5745.
Target Overview
Tumor cells with compromised DNA repair mechanisms (such as loss of BRCA1 or BRCA2 function, affecting double-strand break repair through homologous recombination), rely on the activity of alternative repair mechanisms for survival – an approach successfully exploited therapeutically using PARP inhibitors, which block single-strand break repair.1,2
An alternative DNA repair mechanism required for the survival of homologous recombination repair (HRR) defective cells is microhomology-mediated end joining (MMEJ), a pathway controlled by the activity of DNA polymerase theta (Polθ, POLQ).3,4 MMEJ repair is also responsible of causing secondary reversion mutations in HRR genes, the best-characterised mechanism of resistance to PARP inhibitors in the clinic.5,6
Inhibition of POLQ with AZD4956 leads to an increase in unrepaired DNA breaks caused by PARP inhibition, enhancing cancer cell death in tumors with HRR defects.7,8
Compound Overview
AZD4956 is an investigational inhibitor of POLQ. It is designed to selectively inhibit the DNA polymerase activity of POLQ to improve the efficacy of PARP inhibitors by increasing the accumulation of DNA damage and preventing the acquisition of PARP inhibitor resistance in tumors with HRR defects. Low expression of POLQ in normal tissue predicts minimal impact of AZD4956 on the toxicity profile of PARP inhibitor treatment.7,8
Mechanism of Action
References
1. Pommier Y, O’Connor MJ, De Bono J. Science translational medicine. 2016;8(362):362ps17. 2. Yap TA, Manning HC, Sapra P, Mills GB, O’Connor MJ. Cell. 2026;189(8):2278-306. 3. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. Nature. 2015;518(7538):258. 4. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. Nature. 2015;518(7538):254-257. 5. Pettitt SJ, Frankum JR, Punta M, Lise S, Alexander J, Chen Y, et al. Cancer discovery. 2020;10(10):1475-1488. 6. Tobalina L, Armenia J, Irving E, O'Connor MJ, Forment JV. Annals of Oncology. 2021;32(1):103-112. 7. Forment JV, Mulderrig L, de Renty C, Southgate H, Jones G, Gesu M, et al. Cancer Research. 2026;86(7_Supplement):230. 8. Barlaam B, Forment JV, Mulderrig L, Christelle DR, Southgate H, Hughes A, et al. Cancer Research. 2026;86(7_Supplement):5745.
Clinical trial information
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PARTHENON trial overview
Abbreviations
BRCA
breast cancer susceptibility gene
PARP
poly (ADP-ribose) polymerase
HRR
homologous recombination repair
MMEJ
microhomology-mediated end joining
POLQ
DNA polymerase theta