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Targeting chromosomal instability in patients with cancer

  • Review Article
  • Published:

From Nature Reviews Clinical Oncology

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Abstract

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.

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 vulnerabilities imposed by CIN will create opportunities for the development of a new class of therapies for patients with otherwise difficult-to-treat cancers.

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Fig. 1: CIN drives cancer progression.
Fig. 2: Cellular stress response as a CIN-induced vulnerability.
Fig. 3: Synthetic lethality approaches to targeting CIN-high tumours.
Fig. 4: Immune vulnerabilities induced by CIN.
Fig. 5: Clinical biomarkers and therapeutic strategies to detect CIN in tumour samples.

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Acknowledgements

We thank all members of the Bakhoum laboratory for discussion and comments. We thank the following sources of funding: for S.F.B., National Institutes of Health/National Cancer Institute (grant nos. P50CA247749, DP5OD026395, R01CA256188, R01CA280572, P30CA008748) Department of Defense Era of Hope Award, Burroughs Wellcome Fund, the Pershing Square Sohn Foundation for Cancer Research, the Josie Robertson Foundation, the Mark Foundation for Cancer Research, and the Starr Cancer Consortium; for D.H.A.-R., Mary Kay Ash Foundation, OCRA Mentored Research Award, 1L32MD017781-01, Conquer Cancer Foundation, and Young Investigator Award.

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Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Duaa H. Al-Rawi, Emanuele Lettera, Jun Li, Melody DiBona & Samuel F. Bakhoum

  2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Duaa H. Al-Rawi, Emanuele Lettera, Jun Li, Melody DiBona & Samuel F. Bakhoum

  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Duaa H. Al-Rawi

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All authors researched data for this article and made a substantial contribution to discussions of content. D.H.A.-R., E.L., J.L. and S.F.B. wrote the manuscript. All authors reviewed and/or edited the manuscript prior to submission.

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Correspondence to Samuel F. Bakhoum.

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Competing interests

S.F.B. has acted as a consultant and/or adviser of Meliora Therapeutics and Volastra Therapeutics, is a co-inventor on patents related to some of the research described in this manuscript on agents targeting chromosomal instability and the cGAS–STING pathway in patients with advanced-stage cancer (patent numbers WO2019014246A1, US20210130903A1 and EP4208572A1), and is the scientific co-founder of, holds equity in, and receives compensation from Volastra Therapeutics. The other authors declare no competing interests.

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Al-Rawi, D.H., Lettera, E., Li, J. et al. Targeting chromosomal instability in patients with cancer. Nat Rev Clin Oncol 21, 645–659 (2024). https://doi.org/10.1038/s41571-024-00923-w

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