WRN Inhibition Selectively Induces Apoptosis in ARID1A-Mutated Cancers, Enhanced by p21 Co-Inhibition

The ARID1A gene, a crucial subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated across various cancers. Despite its prevalence, effective clinical treatments for patients with ARID1A mutations remain limited, underscoring a significant unmet need for targeted therapeutic strategies. This research investigates Werner syndrome adenosine 5'-triphosphate-dependent helicase (WRN) as a critical and selective vulnerability in these specific cancer types, aiming to exploit differential DNA damage responses for therapeutic benefit.

Researchers employed both genetic and pharmacological inhibition of WRN in ARID1A-mutated and ARID1A-proficient cell lines. They meticulously assessed the impact on Chk1-mediated DNA damage signaling, subsequent Chk2 activation, cell cycle progression (specifically G1 vs G2-M arrest), and induction of apoptosis. To further enhance cytotoxicity, they explored the effect of additional p21 inhibition in WRN-suppressed ARID1A-mutated cells. The antitumor efficacy of WRN inhibition alone and in combination with p21 inhibition was rigorously validated using both cell line-based xenograft and patient-derived xenograft (PDX) mouse models.

Upon genetic and pharmacological WRN inhibition, ARID1A-mutated cells exhibited defective checkpoint kinase 1 (Chk1)-mediated DNA damage signaling. This defect led to a compensatory checkpoint kinase 2 (Chk2) activation, culminating in G1 phase arrest and subsequent apoptosis specifically in ARID1A-mutated cells. This response highlighted a selective vulnerability.

In stark contrast, ARID1A-proficient cells, when subjected to WRN inhibition, underwent a Chk1-dependent G2-M arrest, demonstrating a differential DNA damage response. Further investigation revealed that additional p21 inhibition, in the context of WRN suppression, promoted cell cycle reentry of the G1-arrested ARID1A-mutated cells. This reentry resulted in significantly enhanced cytotoxicity through a mechanism termed mitotic catastrophe. The study successfully validated the antitumor efficacy of WRN inhibition, both as a monotherapy and in combination with p21 inhibition, across cell line-based xenograft and patient-derived xenograft mouse models.