Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition

A fraction of cancer cells are highly dependent on kinesin KIF18A function because of alterations in the ratio of APC/C and spindle assembly checkpoint (SAC) signals.

The kinesin KIF18A has emerged as an important new drug target, but why ~25% of cancers are addicted to this protein remains unclear.

This work provides a mechanistic model implicating altered APC/C activity and spindle assembly checkpoint (SAC) signaling in the cancer cell-specific dependence on KIF18A.

KIF18A inhibition weakens kinetochore-microtubule interactions, leading to modest but widespread SAC activation in both KIF18A-dependent and KIF18A-agnostic cell lines.

Genome-wide CRISPR-Cas9 screens demonstrate that reducing the barrier to mitotic exit or stabilizing kinetochore-microtubule interactions relieves KIF18A inhibitor toxicity.

Whole genome doubling magnifies total SAC output after KIF18A inhibition, increasing the probability of lethal mitotic delays.

APC/C deficiency is a strong driver of KIF18A dependency, and genetically engineering hyperploidy and low APC/C activity synergistically generates strong KIF18A dependence in otherwise insensitive cells.

KIF18A-dependent cells exhibit SAC:APC/C imbalance, including slow metaphase-to-anaphase transition, long overall mitotic duration, and delayed cyclin B1 degradation Sensitivity to depletion of APC/C genes is the strongest correlate for KIF18A dependency in the 550+ cell line Broad DepMap cancer database.

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues.

A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target.

Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear.

Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays.

Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition.

KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall.

Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.