Targeting WEE1 in <i>ARID1A/TP53</i> Concurrent Mutant Colorectal Cancer by Exploiting R‐Loop Accumulation and DNA Repair Deficiencies

ARID1A, a component of the SWI/SNF tumor suppressor complex, is frequently mutated in colorectal cancers (CRC). Here, it is found that CRC with ARID1A/TP53 concurrent mutations is highly sensitive to WEE1 inhibitors. ARID1A deficiency promoted the accumulation of R-loops, leading to replication stress. This stress, combined with the loss of G1/S and G2/M checkpoint controls due to P53 and WEE1 dysfunction, resulted in substantial DNA damage. Through chromatin accessibility sequencing, it is further revealed that ARID1A loss impaired ATF3 transcription, thereby exacerbating WEE1-inhibitor-induced DNA damage and cell death. This preclinical evidence is supported by a phase 1b/2 trial of WEE1-inhibitor-based therapy in metastatic CRC patients (NCT06363552), where one patient harboring ARID1A/TP53 concurrent mutations achieved liver lesion regression. Moreover, though CRISPR knockout screening, it is found that concurrent AKT blockade significantly augmented the antitumor effects of the WEE1 inhibitor. In conclusion, WEE1 inhibition offers a promising therapeutic strategy for ARID1A/TP53 concurrent mutant CRC.

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Publication Details

Journal
Advanced Science
Published
2025-11-30
DOI
https://doi.org/10.1002/advs.202512074
Citations
2
Primary Topic
Chromatin Remodeling and Cancer
Type
article
Field-Weighted Citation Impact
1.61
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article

Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R‐Loop Accumulation and DNA Repair Deficiencies

Luoyan Ai, Yiyi Yu, T.-S. Liu, Qihong Huang et al.
2 citations
Advanced Science
Chromatin Remodeling and Cancer
1.61
article

Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R‐Loop Accumulation and DNA Repair Deficiencies

Luoyan Ai, Yiyi Yu, T.-S. Liu, Qihong Huang, Ke Peng, Qing Liu, Jianhua Wang, Chi Zhang, Haojie Zhou, Xiaojing Xu, Shan Yu, Huishan Li, Mengling Liu, Meng-Xuan Zhu, Yanjing Zhu, Yichen Wang, Zhenghang Xu, Yun Liu
article en
2 citations

Abstract

ARID1A, a component of the SWI/SNF tumor suppressor complex, is frequently mutated in colorectal cancers (CRC). Here, it is found that CRC with ARID1A/TP53 concurrent mutations is highly sensitive to WEE1 inhibitors. ARID1A deficiency promoted the accumulation of R-loops, leading to replication stress. This stress, combined with the loss of G1/S and G2/M checkpoint controls due to P53 and WEE1 dysfunction, resulted in substantial DNA damage. Through chromatin accessibility sequencing, it is further revealed that ARID1A loss impaired ATF3 transcription, thereby exacerbating WEE1-inhibitor-induced DNA damage and cell death. This preclinical evidence is supported by a phase 1b/2 trial of WEE1-inhibitor-based therapy in metastatic CRC patients (NCT06363552), where one patient harboring ARID1A/TP53 concurrent mutations achieved liver lesion regression. Moreover, though CRISPR knockout screening, it is found that concurrent AKT blockade significantly augmented the antitumor effects of the WEE1 inhibitor. In conclusion, WEE1 inhibition offers a promising therapeutic strategy for ARID1A/TP53 concurrent mutant CRC.

Advanced ScienceVol. 13(9)
Shanghai Medical College of Fudan University (CN), Sun Yat-sen University (CN), Fudan University (CN), Fudan University Shanghai Cancer Center (CN), Precision for Medicine (United States) (US), Zhongshan Hospital of Xiamen University (CN), Zhongshan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN)
Openalex Percentile: Top 14%
Chromatin Remodeling and Cancer
1.61
DOIOpen Access PDFOpenAlex
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