Journal
BIOMOLECULES
Volume 9, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/biom9080331
Keywords
PI 3-kinase; chromosomal instability; PI3K inhibitor; cancer; tumour evolution; centrosome
Categories
Funding
- Wellcome Trust [210752]
- Cancer Research UK studentship [C416/A25196]
- Cancer Research UK Lung Cancer Centre of Excellence [C7893/A24956]
- Biotechnology and Biological Sciences Research Council [BB/P027067/1]
- Cancer Research UK [C23338/A25722]
- PTEN Research, Cancer Research UK [C23338/A25722]
- UK NIHR University College London Hospitals Biomedical Research Centre
- Ong Hin Tiang & Ong Sek Pek Foundation, Malaysia
- Biotechnology and Biological Sciences Research Council [BB/P027067/1] Funding Source: researchfish
- BBSRC [BB/P027067/1] Funding Source: UKRI
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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 PI3K alpha 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.
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