Oncogenic PIK3CA corrupts growth factor signaling specificity
Ralitsa R Madsen1,2, Alix Le Marois3, Oliwia N Mruk4
1Cell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O'Gorman Building, University College London, London, WC1E 6BT, UK. rmadsen001@dundee.ac.uk.
Molecular Systems Biology
|December 20, 2024
Summary
The PIK3CA^H1047R^ oncogene corrupts growth factor signaling, altering phosphoinositide 3-kinase (PI3K)/AKT pathway information transfer and amplifying specific receptor signals. This finding offers new therapeutic strategies for cancer.
Area of Science:
- Cellular signaling
- Molecular biology
- Cancer research
Background:
- Understanding growth factor signal encoding in the phosphoinositide 3-kinase (PI3K)/AKT pathway is limited by technical challenges.
- The impact of oncogenic mutations on PI3K/AKT pathway signaling fidelity remains unclear.
Purpose of the Study:
- To develop a kinetic, single-cell framework for quantifying PI3K-specific information transfer.
- To investigate how the PIK3CA^H1047R^ oncogene alters growth factor signaling and pathway fidelity.
Main Methods:
- Live-cell imaging of PI3K/AKT activity reporters.
- Multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers.
- Single-cell kinetic framework for information transfer calculations.
Main Results:
- The PIK3CA^H1047R^ oncogene does not act as a simple constitutive activator.
- Dose-dependent PIK3CA^H1047R^ expression corrupted growth factor-induced information transfer fidelity.
- Preferential amplification of epidermal growth factor receptor (EGFR) signaling over IGF1 and insulin receptor signaling was observed.
- PIK3CA^H1047R^ increased both the mean and heterogeneity of signaling responses.
Conclusions:
- Oncogenic PIK3CA^H1047R^ corrupts information transfer in a growth factor-dependent manner.
- This provides new opportunities for therapeutic intervention by tuning receptor-specific PI3K pathway outputs.
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