The potential of Senicapoc, a KCNN4 inhibitor, for the prevention and treatment of breast cancer
The potential of Senicapoc, a KCNN4 inhibitor, for the prevention and treatment of breast cancer
Abstract BackgroundGenome-wide association studies have identified a breast cancer risk locus at 19q13.31. The candidate causal variants at this locus are located in the first exon of KCNN4. KCNN4, which regulates membrane potential and Ca2+ signaling, is a good candidate for drug repositioning because its inhibitor, Senicapoc, has been shown to be well tolerated in Phase-II and -III clinical trials for asthma and sickle cell anemia. MethodsWe evaluated public mRNA expression data to determine whether the allele at 19q13.31 associated with increased breast cancer risk was associated with KCNN4 expression. We also used immunohistochemistry to evaluate the relationship between KCNN4 protein expression and breast cancer survival. We then used Senicapoc in two murine mammary tumor models to determine if it would delay tumor development. We also treated mice bearing 4T1 mammary tumors with Senicapoc, by subcutaneous injection and by oral gavage. Finally we used gene editing to make deletions within Kcnn4 in 4T1 to determine whether Senicapoc had off-target effects on tumor growth. ResultsAnalysis of the Genotype-Tissue Expression Project showed that the allele at 19q13.31 associated with increased breast cancer risk is associated with increased KCNN4 expression, suggesting that inhibiting KCNN4 might reduce breast cancer risk. Using immunohistochemistry in a large breast cancer cohort, we found that membrane and cytoplasmic expression is a marker of poor prognosis in triple negative breast cancer. We then tested the efficacy of Senicapoc to prevent and treat breast cancer. This showed that it delays the development of mammary tumors in two murine models, and slows growth of a syngeneic (4T1) model of triple negative breast cancer. Senicapoc monotherapy showed similar efficacy to anthracycline/taxane-based chemotherapy in these studies, with a stronger effect when they were combined. ConclusionsThese results provide a rationale for clinical testing of Senicapoc for treating, and even preventing, breast cancer.
Pereira Melrine、Ruppert Meagan、Kutasovic Jamie R.、Handoko Herlina Y.、Chen XiaoQing、Chenevix-Trench Georgia、Shi Wei、Beesley Jonathan、Miranda Mariska、Bessette Darrell、Kalinowski Lauren、Britt Kara、Black Debra M.、Carter-Cusack Dylan、McCart Reed Amy E.、Teale Zachary、Al-Ejeh Fares、Saunus Jodi M.、Jackson Susan、Lakhani Sunil R.、MacDonald Kelli、Civitarese Andrew、Xiao Christos
Peter MacCallum Cancer CentrePeter MacCallum Cancer CentreUniversity of Queensland Centre for Clinical Research, Faculty of Medicine, The University of QueenslandQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute Australia||Independent ResearcherUniversity of Queensland Centre for Clinical Research, Faculty of Medicine, The University of QueenslandPeter MacCallum Cancer Centre||Sir Peter MacCallum Department of Oncology, The University of MelbourneQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaUniversity of Queensland Centre for Clinical Research, Faculty of Medicine, The University of QueenslandQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute Australia||Currently at Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar FoundationUniversity of Queensland Centre for Clinical Research, Faculty of Medicine, The University of QueenslandPeter MacCallum Cancer CentreUniversity of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland||The Royal Brisbane & Women?ˉs HospitalQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute AustraliaQIMR Berghofer Medical Research Institute Australia
肿瘤学基础医学药学
KCNN4inhibitorbreast cancerpreventiontreatment
Pereira Melrine,Ruppert Meagan,Kutasovic Jamie R.,Handoko Herlina Y.,Chen XiaoQing,Chenevix-Trench Georgia,Shi Wei,Beesley Jonathan,Miranda Mariska,Bessette Darrell,Kalinowski Lauren,Britt Kara,Black Debra M.,Carter-Cusack Dylan,McCart Reed Amy E.,Teale Zachary,Al-Ejeh Fares,Saunus Jodi M.,Jackson Susan,Lakhani Sunil R.,MacDonald Kelli,Civitarese Andrew,Xiao Christos.The potential of Senicapoc, a KCNN4 inhibitor, for the prevention and treatment of breast cancer[EB/OL].(2025-03-28)[2025-08-16].https://www.biorxiv.org/content/10.1101/2023.04.25.538345.点此复制
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