ArticleAmerican journal of cancer research2020
mTOR inhibition overcomes primary and acquired resistance to Wee1 inhibition by augmenting replication stress in epithelial ovarian cancers.
Article in American journal of cancer research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- An update of predictive biomarkers related to WEE1 inhibition in cancer therapy.Journal of cancer research and clinical oncology · 2024Pooled it
- Phase II Study of Adavosertib in Patients With Tumors Containing BRCA1 and BRCA2 Mutations: Results From the NCI-MATCH ECOG-ACRIN Cancer Research Group (EAY131) Subprotocol Z1I.JCO precision oncology · 2026Trial
- 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
- Discovery of molecularly-informed therapeutic strategies for mature T-cell leukemias and lymphomas.Blood advances · 2025Article
- WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2.Nature communications · 2025Article
- WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASCell death & disease · 2025Article
- Targeting WEE1 Kinase in Gynecological Malignancies.Drug design, development and therapy · 2024Review
- Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders.ACS omega · 2023Review
- ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models.The Journal of clinical investigation · 2023Article
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
- Effects of Wee1 inhibitor adavosertib on patient-derived high-grade serous ovarian cancer cells are multiple and independent of homologous recombination status.Frontiers in oncology · 2022Article
- Article
- A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.Journal of hematology & oncology · 2020Review
- Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation.Journal of hematology & oncology · 2020Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
Epithelial ovarian cancer is characterized by universal TP53 mutations, which result in G1/S checkpoint deficiencies. Therefore, it is hypothesized that the abrogation of the G2/M checkpoint with Wee1 inhibitor might preferentially sensitize TP53-defective ovarian cancer cells. Given the extremely high molecular diversity in ovarian cancer, one approach to improving the clinical efficacy is to identify drug combinations that either broaden the applicable spectrum or circumvent resistance. Here, through a high-throughput unbiased proteomic profiling (RPPA), we found the complementary activated mTOR pathway contributes greatly to Wee1 inhibitor resistance. A combination of Wee1 and mTOR inhibits synergistically inhibiting tumor growth in ovarian cancer cell lines and patient-derived xenograft that closely mimic the heterogeneity of patient tumors. Mechanistically, dual Wee1/mTOR inhibition induced massive DNA replication stress, leading to fork stalling and DNA damage. Moreover, we found that the addition of nucleotide metabolic substrate dNTPs alleviated replication stress, restored the cell cycle and reduced apoptosis to some extent, supporting dNTPs depletion is necessary for the synergy between Wee1 and mTOR inhibits. These results suggest that our study opening up a wider therapeutic window of Wee1 inhibitor for the treatment in epithelial ovarian cancers.
Indexed as
Identifiers
32266099PMC7136919W3014502324What OpenQuestion holds
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 OpenQuestion graph.