Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in ARID1A -mutated cancers
- Jiwon Kim
- Jaeik Oh
- Dongjun Jang
- Seungjae Shin
- Soo-Jin Lee
- Sang Eun Lee
- Yoojin Yang
- Dohee Kim
- Ae Jin Choi
- Hae Rim Jung
- Yumi Oh
- Sung-Yup Cho
2026-06-05
ARID1A (AT-rich interaction domain 1A), a key subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, is frequently mutated in cancers. However, effective clinical treatments for patients with this mutation are limited, highlighting a need for therapeutic strategies. Here, we identify Werner syndrome adenosine 5′-triphosphate–dependent helicase (WRN) as a critical vulnerability in ARID1A -mutated cancers. Upon genetic and pharmacological inhibition of WRN, ARID1A -mutated cells had defective checkpoint kinase 1 (Chk1)-mediated DNA damage signaling, resulting in compensatory checkpoint kinase 2 (Chk2) activation, leading to G 1 phase arrest and apoptosis, whereas ARID1A -proficient cells underwent Chk1-dependent G 2 -M arrest. Additional p21 inhibition in the context of WRN suppression promoted cell cycle reentry of G 1 -arrested ARID1A -mutated cells, resulting in enhanced cytotoxicity through mitotic catastrophe. The antitumor efficacy of WRN inhibition alone and in combination with p21 inhibition was validated using cell line–based xenograft and patient-derived xenograft mouse models. Our findings define WRN as a selective therapeutic target in ARID1A -mutated cancers and suggest a combinatorial strategy of WRN and p21 inhibition as a therapeutic approach.