Targeting chromosomal instability in patients with cancer

Chromosomal instability (CIN) is a hallmark of cancer and a driver of metastatic dissemination, therapeutic resistance, and immune evasion. CIN is present in 60–80% of human cancers and poses a formidable therapeutic challenge as evidenced by the lack of clinically approved drugs that directly target CIN. This limitation in part reflects a lack of well-defined druggable targets as well as a dearth of tractable biomarkers enabling direct assessment and quantification of CIN in patients with cancer. Over the past decade, however, our understanding of the cellular mechanisms and consequences of CIN has greatly expanded, revealing novel therapeutic strategies for the treatment of chromosomally unstable tumours as well as new methods of assessing the dynamic nature of chromosome segregation errors that define CIN. In this Review, we describe advances that have shaped our understanding of CIN from a translational perspective, highlighting both challenges and opportunities in the development of therapeutic interventions for patients with chromosomally unstable cancers. Chromosomal instability (CIN) is a dynamic phenotype characterized by changes in chromosome number and structure and is a hallmark of clinically aggressive malignancies. Nonetheless, the ability of cancer cells to tolerate CIN creates several potential therapeutic vulnerabilities. In this Review, the authors describe the development of CIN and how this phenotype promotes carcinogenesis and tumour progression as well as describing the various attempts to develop targeted therapies based on the specific vulnerabilities of these tumours. Key points Chromosomal instability (CIN) has long been recognized as a hallmark of aggressive human malignancies and research over the past two decades has identified several novel therapeutic approaches for patients with chromosomally unstable cancers. CIN drives cancer progression by generating genomic alterations such as chromosomal gains, losses and complex rearrangements. CIN can also drive the development of epigenetic abnormalities and chronic inflammation that facilitate both metastatic dissemination and immune evasion. The development of synthetic lethal approaches in the context of CIN has led to the development of several novel treatment approaches, including KIF18A inhibitors, p53-reactivating agents and PLK4 inhibitors, all of which are currently being tested in clinical trials. A mechanistic understanding of the cancer cell-intrinsic and immune-related v