Inhibition of KIF20A by BKS0349 reduces endometriotic lesions in a xenograft mouse model

Abstract

Several studies have suggested a possible etiological association between ovarian endometriosis and ovarian cancer. Evidence has shown that KIF20A overexpression might confer a malignant phenotype to ovarian tumors by promoting proliferation and inhibiting apoptosis. However, no data about the role of KIF20A in endometriosis have been described. In this study, the human endometrium (n = 4) was transfected by mCherry adenovirus and intraperitoneally implanted in mice. Subsequently, mice were divided in three groups (n = 8/group) that were treated with Vehicle, BKS0349 (KIF20A-antagonist) or cabergoline (dopamine receptor agonist) for 21 days. mCherry-labeled endometriotic lesions were monitored over time using the IVIS Imaging System. Mice were sacrificed 72 h after the last administration; proliferation was evaluated by immunohistochemistry and apoptosis by TUNEL. CCND1 gene expression (G1 phase-related gene) was measured by qRT-PCR. A significant reduction in mCherry-fluorescent signal was observed in the BKS0349 group after treatment ended (D24) compared with D0 (P-value = 0.0313). Moreover, the mCherry signal on D24 showed a significant decrease in the BKS0349 group compared with controls (P-value = 0.0303), along with significant size reduction of endometriotic lesions observed in the BKS0349 group compared with control on D24 (P-value = 0.0006). Functional studies showed a significant reduction in proliferating cells in the BKS0349-treated group compared with controls (P-value = 0.0082). In addition, CCND1 expression was decreased in the BKS0349 group compared with control (P-value = 0.049) at D24 and a significant increase in apoptotic cells among endometriotic lesions in BKS0349-treated mice was observed compared with control (P-value = 0.0317). Based on these findings, we concluded that BKS0349 induces apoptosis and inhibits cell proliferation, reducing endometriotic lesion size and suggesting KIF20A inhibition by BKS0349 as a novel therapeutic treatment for endometriosis.

MKLP2 functions in early mitosis to ensure proper chromosome congression

“…We report here that MKLP2 functions in early mitosis to promote chromosome congression via correction of syntelic attachments and regulation of Aurora Kinase A (AURKA) and B (AURKB). Our experiments treating cells with second (MKLP2i 2 ) and third (MKLP2i 3 ) generation MKLP2 small molecule inhibitors (Ferrero et al, 2019; Labrière et al, 2016) revealed lagging chromosomes, chromosome bridges, and daughter cells with significantly distinct chromosome numbers, confirming that MKLP2 safeguards cells against aneuploidy.…”

Characterization of KIF20A as a prognostic biomarker and therapeutic target for different subtypes of breast cancer

“…Targeting KIF20A with more selective and potent small molecule inhibitors may be an effective therapeutic strategy for a wide variety of breast cancers. The newly developed, potent KIF20A inhibitor, BKS0349, was recently reported to suppress KIF20A ATPase activity at levels 2-10-fold greater than paprotrain in various cancer cell lines and in a xenograft mouse model without noticeable variation (48,49). Further preclinical studies investigating KIF20A inhibitors are crucial for the development of novel molecular targeted drugs that can be used to treat highly malignant breast cancers, such as TNBC.…”

Role of motor proteins in human cancers

“…Other Kenesins inhibitors include paprotrain and its derivatives . BKS0349, a new paprotrain high affinity derivative, is a KIF20A-specific inhibitor ( Ferrero et al, 2019 ). BKS0349 was shown to be a promising anticancer agent in an experimental mouse model of ovarian endometriosis ( Qiao et al, 2021 ) .…”