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Ref Type Journal Article
PMID (33589588)
Authors Zhang N, Tian YN, Zhou LN, Li MZ, Chen HD, Song SS, Huan XJ, Bao XB, Zhang A, Miao ZH, He JX
Title Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.
Journal Cell death & disease
Vol 12
Issue 2
Date 2021 Feb 15
URL
Abstract Text Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3β and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3β was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable LY2090314 + Niraparib Preclinical - Cell culture Actionable In a preclinical study, treatment with LY2090314 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Zejula (niraparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable LY2090314 + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with LY2090314 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Rubraca (rucaparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable CHIR99021 + Olaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with CHIR99021 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Lynparza (olaparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable CHIR99021 + Simmiparib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of CHIR99021 and Simmiparib resulted in a synergistic effect in colorectal cancer cells with either BRCA1/2 proficiency or BRCA2 deficiency in culture, demonstrating increased cell cycle arrest, apoptotic cell death, and decreased cell survival (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable LY2090314 + Simmiparib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of LY2090314 and Simmiparib resulted in a synergistic effect in colorectal cancer cells with either BRCA1/2 proficiency or BRCA2 deficiency in culture, demonstrating increased cell cycle arrest, apoptotic cell death, and decreased cell survival, and led to inhibition of tumor growth, increased double-strand DNA breaks, and elevated cleaved caspase 3 in cell line xenograft models (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable CHIR99021 + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with CHIR99021 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Rubraca (rucaparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable CHIR99021 + Niraparib Preclinical - Cell culture Actionable In a preclinical study, treatment with CHIR99021 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Zejula (niraparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable LY2090314 + Olaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with LY2090314 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Lynparza (olaparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable CHIR99021 + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, treatment with CHIR99021 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Talzenna (talazoparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588
Unknown unknown colorectal cancer not applicable LY2090314 + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, treatment with LY2090314 sensitized colorectal cancer cell lines with either BRCA1/2 proficiency or BRCA2 deficiency to Talzenna (talazoparib) in culture, resulting in a synergistic effect (PMID: 33589588). 33589588