SCIENCE

Mitosis is the normal process through which our cells divide into two genetically identical cells. This multistep process involves the duplication of chromosomes followed by the perfect division of each chromosome pair into two daughter cells.

Mitosis is very tightly orchestrated in normal cells. If errors occur during this process in healthy cells, a series of controlled checkpoints correct the error or trigger cell death.

Interphase

Prophase

Chromosomes
condense

Metaphase

Chromosomes
line up at midline

Anaphase

Sister chromatids
pulled apart

Telophase
& cytokinesis

Cell pinches
in the middle

Two identical
daughter cells

Chromosomal instability

Cancer cells behave differently from normal cells. They have adapted to divide despite mitotic errors and thus form daughter cells with abnormalities in the structure and number of chromosomes, allowing for the generation of genetic changes and creation of diversity that allows them to evade the body’s normal responses and even cancer therapies. This process which creates high rates during cancer cell division is called chromosomal instability.

Surviving and thriving despite these abnormal mitotic events is not an easy task for cancer cells. In addition to thwarting the numerous checkpoints and controls that prevent these abnormalities, cancer cells must also perform mitosis with chromosomes that have abnormal structures and numbers. To pull off this feat, cancer cells need to make a series of adaptations, often relying on proteins and processes that healthy cells usually don’t need to perform their orderly and controlled mitosis.

KIF18A is one such protein chromosomally unstable cancer cells need to divide, but that is not necessary for the division of normal cells. This cancer cell-specific reliance creates an opportunity to selectively target cancer cell mitosis to stop cancer in its tracks.

KIF18A

KIF18A helps with alignment of chromosomes at the midline of the dividing cell during metaphase so that mitosis can continue.

It works by binding to and influencing the length and stability of microtubules, which are string-like structures within cells that move chromosomes during cell division. Many proteins guide microtubules to connect and pull chromosomes in the right direction at the right time. KIF18A helps to fine-tune the tension of the microtubules. While mitosis of normal cells can be performed without this extra control, chromosomally unstable cancer cells need the help of KIF18A to successfully complete their chaotic process.

KIF18A has garnered significant attention from multiple research groups as a novel target for potential cancer treatments.

References (Nature Journal):

Marquis, C., Fonseca, C.L., Queen, K.A. et al. Chromosomally unstable tumor cells specifically require KIF18A for proliferation. Nat Commun 12, 1213 (2021).

Cohen-Sharir, Y., McFarland, J.M., Abdusamad, M. et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature 590, 486–491 (2021).

Quinton, R.J., DiDomizio, A., Vittoria, M.A. et al. Whole-genome doubling confers unique genetic vulnerabilities on tumour cells. Nature 590, 492–497 (2021).

Using a drug to block KIF18A activity can prevent cancer cells from dividing and proliferating. More specifically, in chromosomally unstable cancer cells, the inhibition of KIF18A prevents chromosome alignment during the metaphase stage, causing mitosis to stall which ultimately leads to cell death.

Lead programs

Volastra is currently advancing two unique and differentiated KIF18A inhibitors in Phase I clinical trials for some of the most difficult to treat types of cancer.

Both of our lead therapeutic programs inhibit the activity of KIF18A, preventing it from performing its function during mitosis. Since normal cells are not reliant on KIF18A the way cancer cells are, selectively and potently targeting this protein allows us to eliminate cancer cells without disrupting the mitosis of healthy cells. This makes KIF18A a highly selective target for fighting cancer.

Although both inhibitors target KIF18A, by designing each one with diﬀerent molecular scaﬀolds we are able to deﬁne two distinct drug proﬁles that we are exploring in the clinic.

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