Abstract A20: Synthetic lethality induced by pharmacological inhibition of ATM and PARP1

DNA double-stranded breaks (DSBs) are highly deleterious and need to be repaired for maintaining genomic stability and viability. Cells resolve DSBs via non-homologous end-joining or homologous recombination repair (HRR). The simultaneous downregulation of both repair mechanisms induces synthetic lethality. Accordingly, PARP1 inhibitors (PARPi) are being used to target cancers with defective HRR such as cancers with BRCA1/2 mutations. Similar to BRCA1/2, ATM is involved in HRR; and ATM deficiency enhances sensitivity towards PARPi. But unlike BRCA1/2, ATM can be targeted using various small-molecule inhibitors (ATMi) in cancers containing wild type ATM. Using nasopharyngeal carcinoma cell lines as models, we found that the combined treatment of PARPi and ATMi led to the accumulation of DSBs, activation of the G2 DNA damage checkpoint, reduced mitotic entry, and diminished cell proliferation. Co-inhibition of ATM and PARP1 induced robust DNA damage responses without triggering mitotic catastrophe. In agreement with this, PARPi induced more DNA damage in ATM-knockout cells than wild type cells. Conversely, ATMi promoted more DNA damage when PARP1 was ablated. Although it is believed that PARPi exerts its effects by both inhibiting PARP1 catalytic activities and trapping PARP1 at DNA breaks, we found that the synergism between ATMi and PARPi did not require PARP1 trapping. These results provide insights on developing combined treatment of PARPi and ATMi into anti-cancer therapie...

Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mak, J. P. Y., Poon, R. Y. C. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research