Exploiting synthetic lethality in PDAC with antibody drug conjugates and ATR inhibition.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with poor prognosis. Antibody-drug conjugates (ADCs) and their combinations with various anti-tumor drugs have made great progress. Camptothecin, and its derivatives (Dxd, SN-38 or exatecan) targeted TOP1 are effective payloads due to their potent anti-tumor activity. ADCs offer a promising avenue, particularly when integrated with synthetic lethality strategies. In this study, the ADC SA-7-49 is engineered by conjugating exatecan to an anti-TROP2 antibody. The synthetic lethality between camptothecin and the ataxia telangiectasia-mutated and rad3-related (ATR) inhibitors in PDAC cells has been identified through a comprehensive screening of DNA damage response pathways. Drug interactions are quantified using Zero interaction potency (ZIP) scores. RNA sequencing is employed to elucidate the mechanisms driving synergistic effects. ATR inhibitors synergize with camptothecin by inducing apoptosis via ATR-Chk1 pathway inhibition. Knockdown of ATR enhances the sensitivity of PDAC cells to camptothecin and SA-7-49. SA-7-49 selectively targets and eradicates PDAC cells and xenografts without side effects, augmenting anti-tumor activity via synthetic lethality. Our findings reveal a novel therapeutic strategy by integrating ADC technology with synthetic lethality in PDAC.