KIF15 (Kinesin-12): molecular biology, physiological functions, and roles in disease

KIF15, a kinesin-12 family motor protein, has emerged as a recurrently upregulated factor in multiple human malignancies and has been implicated in diverse oncogenic processes. This review aims to provide a comprehensive synthesis of the molecular biology of KIF15, its oncogenic and non-oncogenic functions, the regulatory mechanisms governing its expression and activity, and its therapeutic potential across human disease contexts.

A comprehensive literature review was conducted using PubMed, Web of Science, and Scopus to identify studies addressing KIF15 structure, mitotic and non-mitotic functions, cancer-associated mechanisms, pharmacological targeting, and germline disease associations.

KIF15 is frequently upregulated across multiple solid tumors-including lung, breast, prostate, pancreatic, gastric, colorectal, and hepatocellular cancers-and elevated expression is commonly associated with adverse clinical outcomes. Mechanistically, KIF15 activates mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK), phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), and epidermal growth factor receptor (EGFR) signaling, androgen receptor (AR) and its splice variant androgen receptor splice variant 7 (AR-V7) to confer enzalutamide resistance, supports glycolytic reprogramming via phosphoglycerate kinase 1 (PGK1) deubiquitination, and maintains cancer stem cells (CSCs) phenotypes through reactive oxygen species (ROS) suppression. KIF15 additionally mediates adaptive resistance to kinesin-5 (Eg5, also known as KIF11), inhibitors via protein regulator of cytokinesis 1 (PRC1)-dependent antiparallel microtubule bundling. Beyond oncology, germline KIF15 variants have been associated with increased genetic susceptibility to idiopathic pulmonary fibrosis. Several KIF15-directed preclinical probes and proof-of-concept inhibitors have been reported, and dual Eg5/KIF15 inhibition has shown synergistic antitumor effects in experimental models.

KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.