Abstract LB017: Potential role of kinesin family member C1 (KIFC1) in melanoma

Abstract

Abstract According to the Surveillance, Epidemiology, and End Results (SEER) analyses, based on 2017-2019 data, approximately ~2.1 percent of men and women will be diagnosed with melanoma at some point during their lifetime. Melanoma can be fatal if not surgically removed at an early stage, with the 5-year survival being a dismal 29.8% for a stage IV melanoma. Melanoma mortality is primarily due to the distant organ metastases and its resistance to treatment, even with newly developed immunotherapy and/or targeted therapies (BRAF and MEK inhibitors). Thus, the discovery of novel melanoma targets is crucial as they may be able to provide alternative treatment options or be used alone or in combination with current therapies. KIFC1 (kinesin family member C1; also known as HSET, an ortholog in Drosophila melanogaster), a nonessential kinesin motor protein, has an established role in centrosome clustering which is utilized by cancer cells to evade apoptosis and mitotic arrest. This occurs when replicating cells harbor additional centrosomes, a hallmark of cancer. The requirement of KIFC1 in mitosis of cancer cells harboring abnormal centrosomes, but not that of normal cells, makes it a potential drug target for cancer management. The goal of this study was to determine the role and significance of KIFC1 in melanoma. Differential expression analysis of GTEX and TCGA RNA-seq data identified significantly higher levels of KIFC1 in both primary and metastatic melanoma as compared to normal skin. In addition, higher expression of KIFC1 was found to be associated with poorer overall survival of melanoma patients. Furthermore, a quantitative protein estimation with the automated ProteinSimple Jess capillary western blotting system demonstrated higher KIFC1 expression in several melanoma cell lines when compared to normal melanocytes. In addition, we also found significantly increased expression of KIFC1 mRNA in mouse melanoma tumors obtained from the genetically engineered BrafV600E/PtenNULL mice, as compared to the normal skin. Next, we determined the effect of a small molecule KIFC1 inhibitor, AZ82 on A375, G361 and Hs294T melanoma cells. AZ82 is an ATP-competitive inhibitor that binds the KIFC1-microtubule complex, blocking the release of ADP and negating its role as a motor protein. Employing RealTime-Glo MT cell viability assay as well as the endpoint XTT growth assay, we found that AZ82 treatment resulted in a significant growth inhibition of human melanoma cells at 2-3.5 µM concentrations. Additionally, AZ82 treatments resulted in a significant decrease in clonogenic survival in all three human melanoma cell lines. Collectively, our data suggests a potential role of KIFC1 in melanoma progression, and merits further investigation to determine the roles and functional and therapeutic significance of KIFC1 in melanoma. Citation Format: Davis S. Mau, Mary A. Ndiaye, Gabriella R. Zaemisch, Chandra K. Singh, Jess Vera, Sean R. McIlwain, Nihal Ahmad. Potential role of kinesin family member C1 (KIFC1) in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB017.