Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer

Abstract

Background: Novel tuppherapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15-IN-1 and KIF11 inhibitor ispinesib in GC. Methods: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo. Results: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo. Conclusion: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

KIF3C: an emerging biomarker with prognostic and immune implications across pan-cancer types and its experiment validation in gastric cancer

“…Recently, there has been a burgeoning interest in investigating their functions in the realm of cancer progression [ 17 ]. Specifically regarding gastric cancer (GC), an array of KIF members, such as KIF5B [ 18 ], KIF1B [ 19 ], KIF14 [ 20 ], KIF11 [ 21 ], KIF15 [ 21 ], KIF18A [ 22 ], KIF20A [ 23 ], KIF21B [ 24 ], KIF22 [ 25 ], KIF23 [ 26 ], KIF26A [ 27 ], KIF26B [ 28 ], and more, have been recognized for their involvement in the progression of gastric cancer via various mechanisms. Moreover, agents aimed at KIFs have demonstrated substantial potential in the realm of cancer therapy.…”

The prognostic and immune significance of KIF3C in pan-cancer and its relationship with malignant progression of gastric cancer

“…Recently, there has been a burgeoning interest in investigating their functions in the realm of cancer progression [17]. Speci cally regarding gastric cancer (GC), array of KIF members, such as KIF5B [18], KIF1B [19], KIF14 [20], KIF11 [21], KIF15 [21], KIF18A [22], KIF20A [23], KIF21B [24], KIF22 [25], KIF23 [26], KIF26A [27], KIF26B [28], and more, have been recognized for their involvement in the progression of gastric cancer via various mechanisms. Moreover, agents aimed at KIFs have demonstrated substantial potential in the realm of cancer therapy.…”

Mitotic Functions and Characters of KIF11 in Cancers

“…Other results have demonstrated that inhibiting KIF15 hinders tumor cells from developing resistance to KIF11 inhibitors [182]. The simultaneous knockdown of KIF11 and KIF15 represses the proliferation of GC cells, providing an insight into an effective combination therapy strategy [183]. Abbreviation: MM, multiple myeloma; R/R PCM, recurrent/refractory plasma cell leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; RCC, renal cell cancer; BC, breast cancer; HNSCC, head and neck squamous cell carcinoma; OC, ovarian cancer; PC, prostate cancer; NSCLC, non-small-cell lung cancer; LC, liver cancer; CRC, colorectal cancer; NHL, non-Hodgkin's lymphoma; HL, Hodgkin's lymphoma; GEC, gastroesophageal cancer; AC, advanced cancer; SCLC, small-cell lung cancer.…”