The adult-type model answers PLK1 inhibition by making more PLK1 and AURKA
also called AURKA compensation · alisertib rescue · antimitotic feedback
When the adult-type cells were given the PLK1 blocker, they responded by making more of the very machinery being blocked. Adding a second drug against one of those backups restored the effect.
The same thing, for a scientist
Volasertib treatment uncovered negative feedback **only in the bone-marrow model**, through compensatory upregulation of PLK-1 itself and related mitotic genes including AURKA. The poor response was overcome by combining with alisertib. This is a clean example of the compensation axis this graph tracks: the resistance is not mutational, arrives immediately, and is specific to the cell of origin rather than to the fusion.
Why the asymmetry is the interesting part
The same fusion, engineered the same way, in two starting cells, gives compensation in one and not the other. If that holds, then compensation capacity is a property of the cell of origin — which would make it the second mechanism in this graph, after HOXA output and menin dependency, that the fusion inherits from its host rather than imposing on it.
It also cuts the other way for infants. A cell that CANNOT mount the compensatory response is more sensitive to the drug and equally unable to protect itself when the same drug hits its normal counterpart.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Upon volasertib treatment, negative feedback was uncovered only in the human bone marrow (adult-mimicking) model, by compensatory upregulation of PLK-1 and related genes involved in mitosis such as AURKA, and the poor response could be overcome by a combinatorial strategy with the Aurora kinase A inhibitor alisertib.
Only Infant MLL-Rearranged Leukemia Is Susceptible to an Inhibition of Polo-like Kinase 1 (PLK-1) by Volasertib · International Journal of Molecular Sciences 2024What this evidence cannot show
Abstract read; full text not read. 'Only in the huBM model' is a negative in the cord-blood arm, and the sensitivity of the assay to detect a smaller compensatory response there is not stated.
Evidence that argues against this (2)
- Transcriptional upregulation of a drug's target after inhibition is close to universal for mitotic kinases, because arrested cells accumulate in the phase where those genes are highest. Some of the 'compensation' may be cell-cycle composition rather than a feedback programme. Oncofusion knowledge graph (internal analysis) 2026
- AURKA is itself pan-essential in DepMap — −1.210 with 99.4% of lines depleted — so the rescue combination pairs two targets that every dividing cell needs. Overcoming resistance by deepening a shared toxicity is not the same as overcoming it. Oncofusion knowledge graph (internal analysis) 2026