Abstract
Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which—even if occurring in a low fraction of the cell population—might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.
Highlights
We provide a general introduction to PI3K and chromosomal instability, and describe in Section 2 how deregulated PI3K activity can affect chromosomal instability.1.1
We have summarised the evidence for a potential role of PIK3CA activation in the induction and/or tolerance of Chromosomal Instability (CIN)
Such a role could be indirect; for example, by providing survival signals to cope with the cell stress imposed by CIN
Summary
Class I PI3Ks are lipid kinases that signal downstream of tyrosine kinases, G protein-coupled receptors and small GTPases such as Ras, cdc and Rac (Figure 1A) and convert the membrane-bound lipid phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2 ) to phosphatidylinositol(3,4,5)trisphosphate (PI(3,4,5)P3 ; known as PIP3 ). This lipid, together with its degradation product PI(3,4)P2 , regulates downstream signalling cascades involving Akt/PKB, mTORC1/2 and other proteins, inducing anabolic metabolism, cell-cycle progression, migration and pro-survival functions [1,2]. 2 of 182 of 18 dephosphorylation at the 3′ position by the PTEN lipid phosphatase, effectively antagonising PI3K effectively. Dampening of class I PI3K signalling [3]
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