Chromosomal instability (CIN) (a hallmark of human cancer) is caused by persistent errors in chromosome segregation during mitosis. Pharmacological inhibition of the mitotic kinesin KIF18A selectively exploits a mitotic vulnerability for which cancer models with CIN are enriched, which leads to robust anti-cancer effects and durable tumor regression in mice.
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References
Marquis, C. et al. Chromosomally unstable tumor cells specifically require KIF18A for proliferation. Nat. Commun. 12, 1213 (2021). This study shows that KIF18A loss decreases the viability of cancer cells with CIN without affecting diploid cells.
Quinton, R. J. et al. Whole-genome doubling confers unique genetic vulnerabilities on tumour cells. Nature 590, 492–497 (2021). This study revealed that cancer cells that undergo whole-genome doubling are more sensitive to KIF18A loss than are diploid cells.
Cohen-Sharir, Y. et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature 590, 486–449 (2021). This study revealed that cancer cells with elevated aneuploidy are more sensitive to KIF18A loss than are diploid cells.
Tamayo, N. A. et al. Targeting the mitotic kinesin KIF18A in chromosomally unstable cancers: hit optimization toward an in vivo chemical probe. J. Med. Chem. 65, 4972–4990 (2022). This study describes the screen for inhibitors of KIF18A motor activity, the characterization of AM-7710 and early hit optimization.
Govindan, R. et al. Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors. J. Clin. Oncol. 39, TPS5600 (2021). This article describes the design of the AMG 650 phase 1 study.
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05902988 (2023). KIF18A inhibitor VLS-1488 entered the clinic this year and was developed by Volastra Therapeutics.
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This is a summary of: Payton, M. et al. Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers. Nat. Cancer https://doi.org/10.1038/s43018-023-00699-5 (2023).
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Therapeutic targeting of the KIF18A motor protein in cancers with chromosomal instability. Nat Cancer 5, 10–11 (2024). https://doi.org/10.1038/s43018-023-00700-1
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DOI: https://doi.org/10.1038/s43018-023-00700-1
