Exploring the potential of saruparib in overcoming venetoclax resistance in AML

Acute myeloid leukaemia (AML) is a highly aggressive type of blood cancer. In particular, elderly and medically unfit patients face a poor prognosis. Treatment with venetoclax and azacitidine improved the outcome for these patients, yet drug resistance remains a significant issue. Combining the poly (ADP-ribose) polymerase (PARP)1/2 inhibitor talazoparib with venetoclax and azacitidine was suggested as a potential treatment option. However, PARP2 inhibition is associated with haematological toxicities. This study explored the therapeutic potential of the selective PARP1 inhibitor saruparib compared to talazoparib in overcoming venetoclax resistance when administered combined with venetoclax and/or azacitidine. Cytotoxic effects in venetoclax resistant AML cell lines were studied in drug sensitivity assays and time to progression assays mimicking the clinical administration of the drugs. Induction of DNA damage and apoptotic signalling were measured to assess molecular mechanisms upon treatment. The triple combination of saruparib, venetoclax and azacitidine effectively induced DNA damage and apoptotic signalling leading to cell death. Talazoparib combined with venetoclax and/or azacitidine induced slightly higher levels of DNA damage and apoptotic signalling, resulting in lower cell viability. In time to progression assays, the triple combination with saruparib, venetoclax and azacitidine effectively inhibited cell expansion but only for the duration of azacitidine administration, suggesting azacitidine as an essential cytotoxic factor. Conversely, the talazoparib triple combination effectively eradicated AML cells with intrinsic venetoclax resistance, possibly due to the additional effect of PARP2 and/or PARP16 inhibition. This indicates that PARP1 inhibition in combination with venetoclax and azacitidine might not be sufficient to overcome venetoclax resistance.
One of the major challenges in treating cancer is drug resistance. Either patients do not respond initially to treatments, or they develop resistance after a few treatment cycles. In this project, the new drug saruparib was tested as a way to overcome drug resistance in acute myeloid leukaemia. While saruparib alone was not effective, combining saruparib with the currently used drugs venetoclax and azacitidine significantly decreased the number of cancer cells. Acute myeloid leukaemia is a highly aggressive type of blood cancer that mainly affects the elderly population. Without treatment, the disease is fatal within a few months. The standard of care is intensive chemotherapy, but this is not tolerated by elderly and medically unfit patients. These patients are instead treated with a combination of azacitidine for 7 days and venetoclax for 28 days. However, most patients end up developing resistance to venetoclax. Therefore, new treatment options are needed for these patients. One possible treatment is the new drug saruparib which selectively targets PARP1, a protein that is involved in DNA damage repair. It has previously been shown that venetoclax causes DNA damage in venetoclax resistant cells. Therefore, targeting DNA repair pathways should lead to accumulation of DNA breaks which should eventually become intolerable for the cancer cells and lead to cell death. This project tested if saruparib increased DNA damage and if this led to cell death. Saruparib was tested alone and combined with venetoclax and/or azacitidine to see if these enhanced the effect of saruparib. It was found that saruparib alone did not increase DNA damage or cause cell death. However, combining saruparib with venetoclax and/or azacitidine enhanced the effect of saruparib. The triple combination with saruparib, venetoclax and azacitidine led to the highest levels of DNA damage and cell death. Azacitidine enhanced the effect of saruparib more than venetoclax since both drugs led to increase