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

  • Nat Cancer. 2023 Dec 27. doi: 10.1038/s43018-023-00699-5.
Marc Payton  1 ,  Brian Belmontes  2 ,  Kelly Hanestad  2 ,  Jodi Moriguchi  2 ,  Kui Chen  3 ,  John D McCarter  3 ,  Grace Chung  2 ,  Maria Stefania Ninniri  2 ,  Jan Sun  2 ,  Raffi Manoukian  4 ,  Stuart Chambers  5 ,  Seok-Man Ho  5 ,  Robert J M Kurzeja  6 ,  Katheryne Z Edson  7 ,  Upendra P Dahal  8 ,  Tian Wu  9 ,  Sharon Wannberg  10 ,  Pedro J Beltran  2 ,  Jude Canon  2 ,  Andrew S Boghossian  11 ,  Matthew G Rees  11 ,  Melissa M Ronan  11 ,  Jennifer A Roth  11 ,  Sheroy Minocherhomji  12 ,  Matthew P Bourbeau  13 ,  Jennifer R Allen  13 ,  Angela Coxon  2 ,  Nuria A Tamayo  13 ,  Paul E Hughes  2
Affiliations
  • 1. Oncology Research, Amgen Research, Thousand Oaks, CA, USA. [email protected].
  • 2. Oncology Research, Amgen Research, Thousand Oaks, CA, USA.
  • 3. Lead Discovery and Characterization, Amgen Research, Thousand Oaks, CA, USA.
  • 4. Cytometry Sciences, Amgen Research, Cambridge, MA, USA.
  • 5. Research Biomics, Amgen Research, San Francisco, CA, USA.
  • 6. Protein Technologies, Amgen Research, Thousand Oaks, CA, USA.
  • 7. PKDM, Amgen Research, Thousand Oaks, CA, USA.
  • 8. PKDM, Amgen Research, San Francisco, CA, USA.
  • 9. Pre-Pivotal Drug Product, Amgen Process Development, Thousand Oaks, CA, USA.
  • 10. Inflammation, Amgen Research, Thousand Oaks, CA, USA.
  • 11. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 12. Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA.
  • 13. Medicinal Chemistry, Amgen Research, Thousand Oaks, CA, USA.
PMID: 38151625 DOI: 10.1038/s43018-023-00699-5
Abstract

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.

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