WCLC 2025 - Posters & ePosters-P2.10.17 Dual PARG-TOP1 Inhibition Exacerbates Dna-Protein Crosslinks and Replication Stress: A Promising Strategy for Enhancing Top1i-ADC Efficacy

P2.10.17 Dual PARG-TOP1 Inhibition Exacerbates Dna-Protein Crosslinks and Replication Stress: A Promising Strategy for Enhancing Top1i-ADC Efficacy

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This document presents preclinical research on IDE161, a potent, selective, orally bioavailable small molecule inhibitor of Poly (ADP-Ribose) glycohydrolase (PARG), a key enzyme involved in DNA damage response and replication fork restart. IDE161 demonstrates selective cytotoxicity in cancer cell lines with DNA repair deficiencies and replication stress, serving as a promising anti-cancer therapy in biomarker-defined patient populations.<br /><br />Key findings include that IDE161 induces persistent replication stress hallmarks—fork slowing, single-stranded DNA gap accumulation, transcription-replication conflicts, and checkpoint activation (ATM/ATR)—resulting in replication fork collapse and cell death. Mechanistically, IDE161 impairs resolution of TOP1-DNA cleavage complexes (Top1cc), enzymatic DNA-protein crosslinks stabilized by Topoisomerase I inhibitors (TOP1i), thus amplifying TOP1i-induced DNA damage.<br /><br />IDE161 synergizes with TOP1 inhibitors such as topotecan and TOP1i-based antibody-drug conjugates (ADCs), including the clinical candidate IDE849 (SHR-4849), which targets DLL3 expressed in ~85% of small cell lung cancer (SCLC). IDE161 enhances tumor responses in models resistant to TOP1i therapies due to low antigen expression by exacerbating TOP1cc accumulation and replication fork failure. Combination treatment yields deep, durable tumor regressions in multiple lineages (SCLC, ovarian, NSCLC) without significant toxicity.<br /><br />CRISPR screens and gene set enrichment analyses identify DNA repair and lagging strand synthesis defects as biomarkers predictive of IDE161 sensitivity. IDE161 also stabilizes PARylated PARP1 and PAR-RECQ1 complexes, disrupting replication fork restart. Pharmacokinetic and efficacy studies support IDE161 as a backbone combination partner for TOP1i payload ADCs to improve therapeutic window and overcome payload delivery limitations.<br /><br />Overall, the data support a novel therapeutic strategy that combines PARG inhibition with TOP1i or TOP1i-ADCs to selectively induce lethal DNA damage and replication catastrophe in tumors with replication stress or DNA repair vulnerabilities. This approach may broaden clinical benefit for TOP1i-ADC therapies across diverse cancer types, including those with low target antigen expression.

Asset Subtitle

Reeja Maskey

Meta Tag

Speaker Reeja Maskey

Topic Metastatic Non-small Cell Lung Cancer – Cytotoxic Therapy

Keywords

IDE161

PARG inhibitor

DNA damage response

replication fork restart

TOP1 inhibitor synergy

replication stress

small cell lung cancer (SCLC)

antibody-drug conjugates (ADCs)

DNA repair deficiency

CRISPR screen biomarkers