Background
Aneuploidy is a hallmark of cancer associated with tumorigenesis 1. However, whether aneuploidy in cancer
generates any clinically relevant vulnerability remains unclear. Unlike normal cells that are generally euploid 2,
cancer cells are almost invariably aneuploid 3. Therefore, the identification of drugs that target aneuploidy has long
been a goal of cancer research. Accumulating evidence suggests that drugs enhancing aneuploidy in cancer cells
already carrying an abnormal chromosome count, i.e. compounds targeting cell cycle as well as spindle assembly
checkpoint (SAC) proteins, can force cancer cells beyond a critical threshold, leading to mitotic catastrophe and
cell death 4,5. In addition, enhancing aneuploidy might favour chromosomal instability (CIN) and prosenescence/
inflammatory pathways, modulating the immune response 6. Our previous work demonstrated that loss
of class II phosphoinositide 3-OH kinase α (PI3K-C2α) causes defective chromosome congression, delayed
anaphase onset and aneuploidy, leading to genomic instability in breast cancer 7,8. Furthermore, we showed that
the production of phosphatidylinositol 3,4-bisphate [PI(3,4)P2] and its precursor PI(4)P by PI3K-C2α and
Phosphatidylinositol 4-Kinase Alpha (PI4KA), respectively, is required for completion of cytokinesis 9. Our
preliminary results indicate that inhibition of PI4KA leads to rapid cell refusion during early cytokinesis and
consequent tetraploidization as well as CIN. Tetraploidization is the first step leading to aneuploidy priming to
cancer onset/progression, but abnormal chromosome counts beyond a certain threshold might define a cancer
specific weakness. In breast cancer, publicly available databases
show that reduced PI4KA mRNA expression can be found in
39.6% of patients and remarkably correlates with an increased
score of aneuploidy (see Figure, left and central). In addition,
among breast cancer subtypes, PI4KA mRNA levels are
significantly reduced in triple negative breast cancer (TNBC) cells
(see Figure, right). Nonetheless, whether and how decreased
PI4KA levels impact on breast cancer prognosis and treatment
efficacy is currently unknown.
Hypothesis
Aneuploidy is a hallmark of cancer contributing to its progression. However, aneuploidy cannot increase beyond
a certain threshold, lethal to the affected cells. In addition, aneuploidy favours the emergence of CIN leading to
modulation of the immune response. Therefore, we hypothesize that, in breast cancer, low PI4KA expression might
increase sensitivity to specific chemotherapeutic agents and modulators acting on mitotic as well as immune
checkpoints, respectively. In addition, by inducing early cytokinesis failure and cell refusion, through PI4KA
inhibition in PI4KA high cancer cells, we expect to elicit CIN and trigger consequent modulation of the anticancer
immune response. Finally, we hypothesize that CIN induced by PI4KA inhibition might synergize with anticancer
drugs targeting chromosome segregation leading to mitotic catastrophe.
General aim
The experimental approaches summarized hereafter will contribute to the identification of new strategies aimed to
increase sensitivity to chemotherapeutics and immune modulators in breast cancer cells in conditions of enhanced
burden of aneuploidy. We will optimize the tolerability of PI4KA inhibitors by testing very low doses still effective
on cell refusion but sufficient to avoid toxicity and exploit this effect in combination with other drugs with the aim
of enhancing aneuploidy beyond the survival threshold.
This project will benefit from established collaborations at the University of Milan-IEO with Prof. Salvatore Pece
(h-index 28), expert in the field of breast cancer, and with Prof. Tamas Balla (h-index 69) at NIH, expert of PI4KA
biology and pharmacology. The project will address the following specific aims:
1) Define the molecular