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

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.

Microtubule poleward flux as a target for modifying chromosome segregation errors

“…by affecting KIF18A, we speculate that it may be possible to increase the rate of chromosome missegregation beyond the tolerable threshold and promote cancer cell death (Cosper et al, 2022; Janssen et al, 2009; Kops et al, 2004). With the recent development of small-molecule inhibitors targeting KIF18A and their encouraging preclinical efficacy observed in certain human cancer models (Gliech et al, 2024; Payton et al, 2023), our study suggests that the misalignment of chromosomes together with elongation of antiparallel overlaps and spindles in cancer cells compared to their non-cancer counterparts, may signal vulnerability to KIF18A inhibition. These biophysical markers could serve as a basis for developing synthetic lethality strategies that include KIF18A inhibition, aiming to selectively eliminate cells exhibiting elevated microtubule poleward flux.…”

Chromosome alignment relies on spindle-localized control of Cdk1 activity

“…Together, our data suggest a scenario in which the distribution of i-Cdk1 along spindle MTs allows Kif18A to be locally dephosphorylated by PP1 in order to regain its ability to concentrate at K-MT plus ends, dampen MT dynamics, and promote chromosome alignment. Although loss of Kif18A function appears to be tolerated by euploid cells, it does appear to be essential for survival of some aneuploid cancers, revealing a strong antitumor therapeutic potential [2,3,[8][9][10][11][12]. In addition, it has been shown that the sensitivity of aneuploid cancer cells to chemical Kif18A inhibition correlates with their ability to delay mitosis exit by implementing an e cient SAC response [12,19,20].…”

“…Although loss of Kif18A function causes micronuclei formation, it appears to be rather tolerated by euploid cells and inactivating mutations in Kif18A have been shown to produce micronuclei in mice without leading to cellular transformation or cancer [2,3,7]. Nevertheless, Kif18A does appear to be essential for survival of aneuploid cancer cells, perhaps by preventing unbearable chromosome mis-segregation in cells with more complicated spindle architecture, and appears a vulnerability target for certain aneuploid cancers [8, 9,10,11,12]. The ability of Kif18A to reach the K-MT plus ends and dampen chromosome oscillations has been shown to be antagonized by phosphorylation operated by Cdk1 and stimulated by its reversal operated by PP1 [13].…”

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

“…5 For instance, omeprazole is a common proton pump inhibitor, 6 Ibrutinib has been used as a powerful BTK inhibitor drug, 7 and AM5308 is a potent kinesin KIF18A inhibitor (Scheme 1B). 8 While pyridines exhibit a planar structure, the 3D architecture of piperidinebased fragments is now widely adopted for lead compound discovery. 9 11 only limited examples focusing on the cycloaddition of BCBs to access racemic BCHeps have been reported (Scheme 1C).…”

“…Nitrogen-containing heterocycles, including pyridines and piperidines, are ubiquitous in pharmaceuticals and serve as fundamental building blocks in organic synthesis . For instance, omeprazole is a common proton pump inhibitor, Ibrutinib has been used as a powerful BTK inhibitor drug, and AM5308 is a potent kinesin KIF18A inhibitor (Scheme B) . While pyridines exhibit a planar structure, the 3D architecture of piperidine-based fragments is now widely adopted for lead compound discovery .…”