Kinesin family member 18A (KIF18A) has emerged as a promising target for cancer treatment, largely because of its central function in cell division and its overexpression in chromosomally unstable tumors. The protein’s highest levels are frequently found to be linked with aggressive cancer development and poor prognosis in patients. The primary function of the protein is to manage microtubule dynamics in mitosis to ensure chromosome alignment and segregation. Because these processes are often aberrant in cancer cells, particularly those with chromosomal instability (CIN), targeting KIF18A represents a compelling approach to selectively inhibit tumor growth without dramatically affecting normal cells.
KIF18A has been found to be overexpressed in a number of solid tumor types, such as breast, ovarian, glioma, pancreatic, and hepatocellular carcinoma. Inhibition of KIF18A results in mitotic defects leading to cell death, which is highly effective against tumors with CIN. In tumors such as glioma and pancreatic adenocarcinoma, KIF18A is involved in the dysregulated proliferation and survival of the cancer cells. Therefore, it is a promising target for therapeutic intervention since the inhibition of KIF18A would interfere with the defective mitotic processes underlying the aggressive progression of these cancers.
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One of the major benefits of KIF18A targeting is its differential expression in cancer and normal cells. Although it is very much expressed in fast-growing cancer cells, normal somatic cells, particularly non-proliferating cells, have low or no KIF18A expression. This selective expression creates a therapeutic window that allows for the targeting of cancer cells with minimal harm to normal tissue.
Apart from its direct function in mitosis, KIF18A also affects the immune microenvironment in certain cancers. For instance, in colorectal carcinoma and glioma, overexpression of KIF18A has been linked with higher tumor mutational burden (TMB) and microsatellite instability (MSI), both of which are correlated with more favorable immune checkpoint inhibitor responses. This indicates that KIF18A could also be involved in modulating the immune landscape of tumors and suggests opportunities for combination therapies targeting both tumor cells and the immune system.
From the therapeutic lens, a few inhibitors of KIF18A are now in the pipeline. A prime example is sovilnesib (AMG650), an oral KIF18A inhibitor being evaluated in clinical trials by Volastra Therapeutics. Early-stage Phase 1b trials in platinum-resistant high-grade serous ovarian cancer (HGSOC) are yielding encouraging results, with favorable tolerability and evidence of efficacy. This prompted the FDA to grant sovilnesib Fast Track designation for HGSOC, highlighting its promise as a novel therapy for hard-to-treat cancers.
Although much of the interest in KIF18A has centered on solid tumors, new work is also investigating its function in hematologic malignancies, including multiple myeloma (MM) and acute myeloid leukemia (AML). In contrast to solid tumors, blood cancers have not universally exhibited elevated KIF18A expression, although recent studies have intimated an association between KIF18A and genomic instability in certain hematologic contexts. Specifically, KIF18A has been recognized as a putative susceptibility gene in MM, wherein overexpression is associated with adverse prognosis and accelerated disease progression. With the genomic instability inherent in hematologic cancers, inhibiting KIF18A may interfere with the mitotic activities in these dividing cells, presenting a potential therapeutic strategy to manage such malignancies as well.
Overall, KIF18A is an attractive therapeutic target, especially in cancers with chromosomal instability. Its involvement in controlling mitosis and its tumor cell selective expression make it a prime target for therapy. Initial-phase clinical trials of inhibitors targeting KIF18A are already showing promising results, and further studies into its potential for use in solid cancers and hematologic malignancies hold much promise. If effective, therapies targeting KIF18A might provide an alternative, more targeted treatment for patients with CIN-driven cancers, hopefully enhancing survival rates and reducing collateral damage to normal tissues.
