自然：三阴性乳腺癌非整倍体新靶点
染色体基因拷贝数量发生变化，可产生非整倍体细胞，这是人类癌症最常见的基因变化。由于癌细胞几乎都是非整倍体，而正常细胞几乎都是整倍体，故非整倍体细胞选择性靶向抑制剂是近年来十分热门的癌症治疗策略之一，尤其对于缺乏靶向治疗药物的三阴性乳腺癌。不过，目前尚不明确人类癌细胞产生非整倍体的具体机制及其治疗靶点。
2021年1月27日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表以色列特拉维夫大学、美国麻省理工哈佛布罗德研究所、哈佛大学达纳法伯癌症研究所、佛蒙特大学、德国凯撒斯劳滕理工大学、意大利米兰大学、欧洲肿瘤研究所、荷兰格罗宁根大学的研究报告，探讨了三阴性乳腺癌等恶性肿瘤产生非整倍体的具体机制及其治疗靶点。
首先，该研究对大约1000种人类癌细胞系的非整倍体基因特征进行分析，并对基因和化学干扰作用进行筛查，以确定非整倍体所致肿瘤弱点。结果发现，非整倍体癌细胞对确保有丝分裂期间染色体正确分离的纺锤体装配检查点核心组件基因干扰敏感性显著较高。
随后，该研究还出乎意料地发现，对于三阴性乳腺癌等恶性肿瘤，非整倍体癌细胞与二倍体癌细胞相比，对短时间暴露于多种纺锤体装配检查点抑制剂的敏感性显著较低。实际上，随着时间延长，非整倍体癌细胞对纺锤体装配检查点抑制剂越来越敏感。非整倍体细胞表现出异常的纺锤体几何形状和动力学，并且纺锤体装配检查点被抑制时保持分裂，造成有丝分裂缺陷越来越多，形成较不稳定且较不匹配的细胞核型。虽然非二倍体癌细胞与二倍体细胞相比，较容易克服纺锤体装配检查点抑制剂，但是其长期繁殖受到抑制。
最后，该研究确定非整倍体癌细胞有丝分裂驱动蛋白KIF18A活性受到干扰。耗尽KIF18A可显著抑制非整倍体癌细胞，而KIF18A过表达可恢复其对纺锤体装配检查点抑制剂的反应。
因此，该研究结果表明，非整倍体与纺锤体装配检查点之间合成致死相互作用具有治疗意义，非整倍体可使癌细胞对有丝分裂检查点抑制剂敏感，KIF18A有望成为三阴性乳腺癌等非整倍体恶性肿瘤的新靶点。
Nature. 2021 Jan 27. Online ahead of print.
Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition.
Yael Cohen-Sharir, James M. McFarland, Mai Abdusamad, Carolyn Marquis, Sara V. Bernhard, Mariya Kazachkova, Helen Tang, Marica R. Ippolito, Kathrin Laue, Johanna Zerbib, Heidi L. H. Malaby, Andrew Jones, Lisa-Marie Stautmeister, Irena Bockaj, René Wardenaar, Nicholas Lyons, Ankur Nagaraja, Adam J. Bass, Diana C. J. Spierings, Floris Foijer, Rameen Beroukhim, Stefano Santaguida, Todd R. Golub, Jason Stumpff, Zuzana Storchová, Uri Ben-David.
Tel Aviv University, Tel Aviv, Israel; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA; University of Vermont, Burlington, VT, USA; TU Kaiserlautern, Kaiserlautern, Germany; European Institute of Oncology, Milan, Italy; University of Milan, Milan, Italy; University of Groningen, Groningen, The Netherlands.
Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analysed genetic and chemical perturbation screens to identify cellular vulnerabilities associated with aneuploidy. We found that aneuploid cancer cells show increased sensitivity to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Unexpectedly, we also found that aneuploid cancer cells were less sensitive than diploid cells to short-term exposure to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects, and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition. Our results identify a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC.
DOI: 10.1038/s41586-020-03114-6