Therapeutic Impact of Homologous Recombination Repair (HRR) or Nucleotide Excision Repair (NER) Deficiency Pertaining to Antibody Drug Conjugate (ADC) Payloads in Urothelial Cancer

Abstract

Background: Approximately 10% of urothelial cancer (UC) patients have defects in the Nucleotide Excision Repair (NER) pathway and at least another 10% have defects in the Homologous Recombination Repair (HRR) pathway. Tumors with HRR or NER defects are more sensitive to platinum-based chemotherapy due to inability repair platinum-induced DNA damage. Two Antibody Drug Conjugates (ADCs), Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV) are approved for treatment of metastatic UC. The cytotoxic payload attached to SG and EV are SN-38 and Monomethyl auristatin E (MMAE) respectively. SN-38 directly damages DNA through inhibition of Topoisomerase 1 activity during DNA replication whereas MMAE is a potent microtubule disruptor but does not have any direct DNA damaging effects. Given the expanding clinical roles for EV and SG in UC, we wished to 1) test the impact of HRR or NER deficiency on sensitivity to SN-38 and MMAE, and 2) assess the degree of synergy (or antagonism) in cell killing from the combination of SN38 or MMAE or Cisplatin with a PARP, ATR or USP1 inhibitor in both defective and proficient NER/HRR cancer cells respectively. Methods: We assembled a series of isogenic NER- and HRR-proficient/deficient cell pairs and compared sensitivity to SN-38 and MMAE, as well as other clinically relevant agents including cisplatin, the PARP inhibitors olaparib and talazoparib, the ATR inhibitor berzosertib, and the USP1 inhibitor ML323. Results: HRR deficiency sensitizes cells to SN38 and MMAE respectively, whereas NER deficiency does not sensitize cells to SN38 or MMAE. The combination of SN38 and PARPi provides substantial synergy irrespective of HRR or NER status. MMAE and Cisplatin combinations with either PARP, ATR or USP1 inhibition are antagonistic or trend towards antagonism irrespective of NER or HHR status. Conclusion: When used as monotherapy, the type of ADC payload (SN38/Topoisomerase1 inhibitor vs MMAE/microtubule disruptor) may not influence clinical efficacy of ADCs irrespective of HRR or NER status. ADCs with SN38 as the payload may confer substantial therapeutic efficacy when combined with a PARP inhibitor.