Fig. 7.

Combination therapy strategies with PARPi. SSBs generated by CTx or RT are repaired by the BER pathway. PARPi inhibit PARylation and induce PARP trapping and the formation of ssDNA gaps, that may result in DSBs, which may also be caused directly by CTx or RT or by DSBs derived from ICLs first repaired by the FA/BRCA pathway in cooperation with TLS. Cancer cells with deficient HRR due to for instance BRCA1/2 mutations, will repair these DSBs by the c-NHEJ pathway (as the alt-NHEJ will be inhibited by PARPi), resulting in incorrect DSB repair, the accumulation of genomic rearrangements and apoptosis. In contrast, cancer cells with proficient HRR will repair these DSBs leading to cancer cell survival and drug resistance. Moreover, alterations in other components of these involved pathways may allow cancer cells to repair DNA damage and become resistant to PARPi. In consequence, the combination with inhibitors of these altered components may resensitize cancer cells to PARPi. Figure created with BioRender