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

Area of Science:

• Oncology
• Cancer Biology
• Drug Development

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
• Antibody-drug conjugates (ADCs) and synthetic lethality are emerging therapeutic strategies.
• Camptothecin derivatives like exatecan are potent anti-tumor payloads.

Purpose of the Study:

• To investigate the efficacy of a novel ADC, SA-7-49 (exatecan conjugated to an anti-TROP2 antibody), in PDAC.
• To explore the synthetic lethality between camptothecin and ATR inhibitors in PDAC.
• To identify mechanisms of synergy between ATR inhibition and camptothecin-based therapies.

Main Methods:

• Engineered SA-7-49 ADC for PDAC targeting.
• Screened DNA damage response pathways to identify synthetic lethality.
• Utilized Zero Interaction Potency (ZIP) scores to quantify drug interactions.
• Performed RNA sequencing to elucidate synergistic mechanisms.
• Assessed effects of ATR knockdown on PDAC cell sensitivity.

Main Results:

• Identified synthetic lethality between camptothecin and ATR inhibitors in PDAC cells.
• ATR inhibitors synergize with camptothecin by inducing apoptosis via ATR-Chk1 pathway inhibition.
• Knockdown of ATR increased PDAC cell sensitivity to camptothecin and SA-7-49.
• SA-7-49 selectively eradicated PDAC cells and xenografts with no observed side effects.

Conclusions:

• SA-7-49 demonstrates selective targeting and eradication of PDAC.
• Integrating ADC technology with synthetic lethality, specifically ATR inhibition, presents a novel therapeutic strategy for PDAC.
• This approach augments anti-tumor activity and offers a promising new avenue for treating pancreatic cancer.