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crispr/cas9 screening identifies a kinetochore-microtubule dependent mechanism for Aurora-A inhibitor resistance in breast cancer

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Cancer Communications 2021年第2期41卷 121-139页

作者： Ailin Chen Shijun Wen Fang Liu Zijian Zhang Meiling Liu Yuanzhong Wu Bin He Min Yan Tiebang Kang Eric W-F Lam Zifeng Wang Quentin Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China Institute of Cancer Stem Cell Dalian Medical UniversityDalianLiaoning 116044P.R.China Department of Surgery and Cancer Imperial College LondonW120NNLondonUK

Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients.Thus,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome.Methods:Here,we conducted a systematic synthetic lethality crispr/cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237.Then,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with MLN8237.For mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237.Mechanistic studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic catastrophe.We further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth.Conclusions:These findings establish Haspin as a synthetic lethal target and demonstrate CHR-6494 as a potential combin

关键词： alisertib Aurora-A breast cancer CHR-6494 crispr/cas9 screening haspin kinetochoremicrotubule mitotic centromere-associated kinesin synthetic lethal xenograft

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