Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers.

Autor: Payton M; Oncology Research, Amgen Research, Thousand Oaks, CA, USA. mpayton@amgen.com., Belmontes B; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Hanestad K; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Moriguchi J; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Chen K; Lead Discovery and Characterization, Amgen Research, Thousand Oaks, CA, USA., McCarter JD; Lead Discovery and Characterization, Amgen Research, Thousand Oaks, CA, USA., Chung G; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Ninniri MS; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Sun J; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Manoukian R; Cytometry Sciences, Amgen Research, Cambridge, MA, USA., Chambers S; Research Biomics, Amgen Research, San Francisco, CA, USA., Ho SM; Research Biomics, Amgen Research, San Francisco, CA, USA., Kurzeja RJM; Protein Technologies, Amgen Research, Thousand Oaks, CA, USA., Edson KZ; PKDM, Amgen Research, Thousand Oaks, CA, USA., Dahal UP; PKDM, Amgen Research, San Francisco, CA, USA., Wu T; Pre-Pivotal Drug Product, Amgen Process Development, Thousand Oaks, CA, USA., Wannberg S; Inflammation, Amgen Research, Thousand Oaks, CA, USA., Beltran PJ; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Canon J; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Boghossian AS; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rees MG; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ronan MM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Roth JA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Minocherhomji S; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA., Bourbeau MP; Medicinal Chemistry, Amgen Research, Thousand Oaks, CA, USA., Allen JR; Medicinal Chemistry, Amgen Research, Thousand Oaks, CA, USA., Coxon A; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Tamayo NA; Medicinal Chemistry, Amgen Research, Thousand Oaks, CA, USA., Hughes PE; Oncology Research, Amgen Research, Thousand Oaks, CA, USA.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Jan; Vol. 5 (1), pp. 66-84. Date of Electronic Publication: 2023 Dec 27.
DOI: 10.1038/s43018-023-00699-5
Abstrakt: Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.
(© 2023. The Author(s).)
Databáze: MEDLINE
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