Targeting Kinesins for Therapeutic Exploitation of Chromosomal Instability in Lung Cancer

Abstract

New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or "targeting kinesins", holds great potential as an effective strategy for treating lung cancer.

Keywords: chromosomal instability; kinesin; lung cancer; targeted therapy.

Figure 1

Timeline indicating the roles of kinesins in mitosis. Kinesins are involved in several critical processes during mitosis, including spindle formation, chromosome condensation, pole separation, chromosome attachment to the spindle, chromosome congression, alignment, and segregation, as well as cytokinesis. Mitotic kinesins contribute to these processes by transporting chromosomes, positioning spindle poles and microtubules, exerting push and pull forces on spindle microtubules by “walking” along them, regulating microtubule dynamics, and attaching kinetochores to K-fibres of the spindle. Note, increments between ticks of the timeline do not represent relative time intervals between subsequent stages of mitosis.

Figure 2

Therapeutic concept for targeting kinesins to exploit chromosomal instability (CIN) in cancer cells. Inhibition of kinesin function induces mitotic stresses, including but not limited to monopolar and multipolar spindle formation and cytokinesis failure. These abnormalities can cause severe chromosome segregation errors and aneuploidies that potentiate CIN beyond tolerable levels, leading to mitotic catastrophe and cell death immediately or upon subsequent cell divisions. Blue dots outside the nucleus indicate micronuclei.