PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• DNA replication stress (RS) is common in cancers and increases sensitivity to ATR inhibitors (ATRis).
• SWI/SNF complex-deficient cancers, like those with SMARCA4 mutations, are particularly vulnerable to DNA damage.
• Identifying synergistic drug combinations is crucial for effective cancer therapy.

Purpose of the Study:

• To screen for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity in SWI/SNF complex-deficient cells.
• To investigate the synergistic effect of ATR inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPi) in SMARCA4-deficient cancers.
• To elucidate the underlying mechanisms of ATRi and PARPi synergy.

Main Methods:

• Screening of DNA damage response inhibitors for synergy with ATRis in SWI/SNF-deficient cells.
• Treatment of SMARCA4-deficient cancer cells with combined ATRi and PARPi.
• Analysis of DNA damage, replication fork progression, and chromatin modifications (H3K9me2).
• In vivo studies using SMARCA4-deficient lung adenocarcinoma xenograft models.

Main Results:

• A potent synergy was identified between ATRi and PARPi, particularly in SMARCA4-deficient cells.
• PARP inhibition led to increased histone H3 lysine 9 di-methylation (H3K9me2), promoting facultative heterochromatin and increasing ATR dependence.
• Combined ATRi and PARPi treatment exacerbated DNA damage in SMARCA4-deficient cells via Mre11 and Mus81.
• In vivo, the combination therapy significantly inhibited tumor growth in xenograft models.

Conclusions:

• PARPi-induced heterochromatin formation amplifies replication stress and ATRi susceptibility.
• The combination of ATRi and PARPi presents a promising therapeutic strategy for SMARCA4-deficient tumors.
• This study provides a mechanistic rationale for targeting SMARCA4-deficient cancers with combined ATRi and PARPi therapy.