Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Therapy resistance remains a major clinical challenge, highlighting the need for new treatments. KIF11 – a mitosis-specific kinesin – is upregulated in various cancers and linked to poor prognosis. Here, we explored role of KIF11 in NSCLC and its potential as a therapeutic target.
Bioinformatic analysis revealed a strong association of KIF11 expression with poor NSCLC patient survival, irrespective of the genetic driver mutations. To evaluate its therapeutic potential, we treated a panel of NSCLC cell lines with the specific KIF11 inhibitor Filanesib (KIF11i). All cell lines responded to KIF11i with strong mitotic arrest. However, the level of cell death was variable between cell lines. We found that some cell lines undergo robust mitotic slippage – exiting mitosis without division – and continue to proliferate, independent of the p53 status. Notably, the resulting hyperploid cells exhibited increased resistance to chemotherapy compared to their diploid counterparts, highlighting potential drawbacks of KIF11 inhibitor monotherapy.
Pro-survival BCL-2 family proteins such as BCL-XL and MCL-1 play an important role in regulating cell fate decision upon mitotic stress. Using an endogenous fluorescent BCL-XL reporter system, we found that KIF11i treatment induces an up-regulation of BCL-XL in slippage-prone cells. Thus, we evaluated whether co-targeting BCL-XL or MCL-1 can prevent mitotic slippage upon KIF11i treatment and promote lung cancer cell killing. Indeed, combination of KIF11i with BCL-XL-targeting PROTAC DT2216 or MCL-1-specific BH3 mimetics induced efficient cell death. Time-lapse microscopy revealed that co-inhibition of BCL-XL effectively eliminates cells in mitotic arrest, while MCL-1 inhibition reduces the number of slipping cells by targeting those that prematurely exit mitosis and re-enter interphase without completing cytokinesis. This highlights the complementary yet distinct roles of the pro-survival proteins during mitotic stress.
Together, KIF11 represents a promising therapeutic target in NSCLC. However, treatment with KIF11i may promote the formation of hyperploid aggressive subclones contributing to disease progression and treatment resistance. Co-targeting of KIF11 and BCL-XL or MCL-1 might represent an efficient strategy to kill NSCLC cells and prevent the emergence of hyperploid cells, thus representing a promising new treatment approach for NSCLC.