Kinesin-8 Members and Their Potential as Biomarker or Therapeutic Target

Mayer, Thomas; Hauf, Silke

doi:10.1007/978-94-017-9732-0_11

Cited by 1 publication

(2 citation statements)

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“…2a-c). The effects of inhibiting KIF19A motor activity (for example, cilia elongation) are distinct from the phenotypes caused by depletion of KIF18A, indicating that they will not confound our proof-of-concept studies 14,29 . In the absence of MTs, KIF18A inhibitors failed to block basal KIF18A motor activity (Extended Data Fig.…”

Section: Discovery Of Potent and Selective Kif18a Inhibitorsmentioning

confidence: 99%

“…The kinesin 8 family of motor proteins is composed of KIF18A, KIF18B and KIF19A, which have distinct functions in cell division (KIF18A, KIF18B) and cilia length control (KIF19A) 14 . The KIF18A motor homodimer uses ATP hydrolysis to move processively along kinetochore-MT fibers, accumulating at plus-end MT tips during metaphase, and remains localized at the midzone through cytokinesis 14 . In cell line models, genetic depletion of KIF18A leads to increased chromosome oscillation and elongated mitotic spindles [15][16][17] .…”

Section: Discovery Of Potent and Selective Kif18a Inhibitorsmentioning

confidence: 99%

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

Payton,

Belmontes,

Hanestad

et al. 2023

Nat Cancer

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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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Section: Discovery Of Potent and Selective Kif18a Inhibitorsmentioning

confidence: 99%