Targeting The Mitotic Spindle In Chromosomally Unstable Cancers
Targeting the Mitotic spindle with microtubule targeting agents like paclitaxel can activate spindle checkpoints and is effective at eliminating cancer cells; unfortunately, it also affects normal cells. This has led to interest in identifying specific microtubule- or MAP-targeting agents that specifically target cancer cells while sparing normal cells.
In 2021 Three groups identified the motor protein KIF18A as indispensable for mitosis in chromosomally unstable cancer cells but not normal cells
Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition - Cohen-Sharir Y. et. al. Nature 2021
Chromosomally unstable tumor cells specifically require KIF18A for proliferation - Marquis C. et. al. Nat Comm 2021
Whole-genome doubling confers unique genetic vulnerabilities on tumour cells - Quinton R. et. al. Nature 2021
Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers - Payton M et. al. Nature Cancer 2023
Payton et al. show that inhibitors of the KIF18A motor protein selectively kill chromosomally unstable cancer cells while having minimal negative effects on human bone marrow cells.
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Kinesins were first discovered in 1985 when it was observed that a new class of ATPases could cycle on and off microtubules and induce organelle movement along the axons of squid and vertebrate brain2,3. Since then, 45 kinesin proteins have been identified in humans, with the Kinesins superfamily (KIF) organized into 14 recognized kinesin families4. Most kinesins have a plus-end directed motility, but motors in the kinesin-14 subfamily have a C-terminal motor and are minus-end directed. The general architecture of kinesins consists of three domains.... click to download the newsletter
The first images of tubulin within the cell began to be observed in the 1950s and 1960s via transmission electron microscopy(1). However, initial fixation methods at that time did not preserve the tubulin structure for it to be observed consistently. Initially, scientists thought these tubulin structures were canaliculi, endoplasmic reticulum, or filamentous elements(2,3). In 1963, after the development of using glutaraldehyde as a fixative, the consistency and resolution of tubulin improved, and the term “microtubules” (MTs) was introduced(4-6). Several years later.... click to download the newsletter