Cancer biology & therapy · 2026
KIF18A inhibitor prevents chromosomally unstable osteosarcoma growth by activating spindle assembly checkpoint.
СтатьяНазвание и аннотация: Перевод в очереди
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Yan Qiang, Zhang Yan, Wang Pengfei, Fu Yahui, Ke Chao, Han Shuang, Xing Jian, Li Haoran, Zhang Kun
Аннотация
BACKGROUND: Osteosarcoma survival rates have not improved significantly in decades, as complex gene mutations and intratumoral heterogeneity hinder new therapy development. To exploit the widespread chromosomal instability in osteosarcoma, we investigated targeting the essential mitotic motor protein KIF18A.
MATERIALS: Two whole-genome-doubling clones derived from the near-diploid SJSA1 osteosarcoma cell line were used to evaluate sensitivity to KIF18A knockout or pharmacological inhibition. The traditional osteosarcoma cell lines U2OS and MG63 were included in the study of the KIF18A inhibitor at both the cellular and xenograft (nude mice) levels.
RESULTS: Depletion of KIF18A significantly reduced cell viability, survival, and proliferation in the SPT cell, but not in the parental SJSA1 cell. Loss of KIF18A expression led to aberrant spindle assembly and mitotic delay through the activation of spindle assembly checkpoint (SAC) signaling. Therefore, the deficiency of SAC rescued the SPT cell growth. We then tested one of the latest KIF18A inhibitors, AM-1882, in SPT, U2OS, and MG63 cells. It showed potent anti-cancer activity and disruption of spindle assembly activity, just like the KIF18A knockout. In the mouse xenograft model, AM-1882 also apparently prevented tumor growth and, notably, did not show any toxicity when compared with chemotherapeutic drugs.
CONCLUSION: Overall, our study demonstrated that KIF18A is a promising therapeutic target in osteosarcoma. The novel inhibitor AM-1882 offers exceptional anti-tumor efficacy paired with a favorable, low-toxicity safety profile.
MATERIALS: Two whole-genome-doubling clones derived from the near-diploid SJSA1 osteosarcoma cell line were used to evaluate sensitivity to KIF18A knockout or pharmacological inhibition. The traditional osteosarcoma cell lines U2OS and MG63 were included in the study of the KIF18A inhibitor at both the cellular and xenograft (nude mice) levels.
RESULTS: Depletion of KIF18A significantly reduced cell viability, survival, and proliferation in the SPT cell, but not in the parental SJSA1 cell. Loss of KIF18A expression led to aberrant spindle assembly and mitotic delay through the activation of spindle assembly checkpoint (SAC) signaling. Therefore, the deficiency of SAC rescued the SPT cell growth. We then tested one of the latest KIF18A inhibitors, AM-1882, in SPT, U2OS, and MG63 cells. It showed potent anti-cancer activity and disruption of spindle assembly activity, just like the KIF18A knockout. In the mouse xenograft model, AM-1882 also apparently prevented tumor growth and, notably, did not show any toxicity when compared with chemotherapeutic drugs.
CONCLUSION: Overall, our study demonstrated that KIF18A is a promising therapeutic target in osteosarcoma. The novel inhibitor AM-1882 offers exceptional anti-tumor efficacy paired with a favorable, low-toxicity safety profile.