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bioRxiv · 10.1101/2025.05.04.652100

Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in ARID1A-mutated cancers

Kim, J.·Oh, J.·Jang, D.·Shin, S.·Lee, S.-J.·Lee, S. E.·Yang, Y.·Kim, D.·Choi, A.-J.·Jung, H. R.·Oh, Y.·Cho, S.-Y.
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Abstract

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancers. However, effective clinical treatments for patients with this mutation are limited, highlighting a demand for new therapeutic strategies. Here, we establish Werner syndrome ATP-dependent helicase (WRN) as a critical vulnerability target in ARID1A-mutated cancers. Upon genetic and pharmacological inhibition of WRN, ARID1A-mutated cells had defective Chk1-mediated DNA damage signaling, resulting in compensatory Chk2 activation, leading to G1-phase arrest and apoptosis, whereas ARID1A-proficient cells underwent Chk1-dependent G2/M arrest. Additional p21 inhibition, combined with WRN suppression, drove G1-arrested cells to re-enter the cell cycle, triggering mitotic catastrophe. The anti-tumor efficacy of WRN inhibition was validated using in vivo cell lines 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.

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Kim, J., Oh, J., Jang, D., Shin, S., Lee, S.-J., Lee, S. E., Yang, Y., Kim, D., Choi, A.-J., Jung, H. R., Oh, Y., Cho, S.-Y.. 2025-05-09. Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in ARID1A-mutated cancers. https://doi.org/10.1101/2025.05.04.652100

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