ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R-Loop Accumulation and DNA Repair Deficiencies.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06363552 (A Study to Evaluate the Preliminary Safety and Efficacy of SC0191 as Single Agent or in Combination With Bevacizumab or 5-FU/LV in Advanced Colorectal Cancer), which is not on this map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Study to Evaluate the Preliminary Safety and Efficacy of SC0191 as Single Agent or in Combination With Bevacizumab or 5-FU/LV in Advanced Colorectal Cancer
Who cites it
6 citing papers in PubMed.
- The roles of chromatin remodeling and 3D genome organization in cancers: from mechanistic insights to emerging treatment options.Molecular cancer · 2026Review
- R-loops and D-loops: a delicate balance in genomic stability and instability.Cell communication and signaling : CCS · 2026Review
- Efficacy and safety of immune checkpoint inhibitors in patients with high microsatellite instability/mismatch repair-deficient advanced cholangiocarcinoma: A propensity score-matched study.JHEP reports : innovation in hepatology · 2026Article
- Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies.Molecular biomedicine · 2026Review
- Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R-Loop Accumulation and DNA Repair Deficiencies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Replication Stress in Cancer: Mechanistic Insights and Therapeutic Opportunities for Radiosensitization.Current issues in molecular biology · 2026Review
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Authors and funding
18 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.