PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models

Molecular Cancer
Lluís NisaMichaela Medová

Abstract

The MET receptor tyrosine kinase represents a promising target in cancer. PIK3CA activating mutations are common in several tumor types and can potentially confer resistance to anti-receptor tyrosine kinase therapy. MET and/or PI3K pathway inhibition was assessed in NIH3T3 cells harboring MET-activating point mutation with or without ectopic expression of PIK3CAE545K and PIK3CAH1047R, as well as in MET-expressing head and neck cancer cells with endogenous PIK3CA mutations. Endpoints included PI3K pathway activation, cell proliferation, colony-forming ability, cell death, wound-healing, and an in vivo model. PIK3CAE545K and PIK3CAH1047R confer resistance to MET inhibition in MET-driven models. PIK3CAH1047R was more potent than PIK3CAE545K at inducing resistance in PI3K pathway activation, cell proliferation, colony-forming ability, induction of cell death and wound-healing upon MET inhibition. Resistance to MET inhibition could be synergistically overcome by co-targeting PI3K. Furthermore, combined MET/PI3K inhibition led to enhanced anti-tumor activity in vivo in tumors harboring PIK3CAH1047R. In head and neck cancer cells the combination of MET/PI3K inhibitors led to more-than-additive effects. PIK3CA mutations can lead to res...Continue Reading

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Citations

Dec 1, 2017·PloS One·Guannan WangDavid B Roth
Jun 28, 2018·Genes & Development·Yu-Han HuangChristopher R Vakoc
Nov 9, 2018·Frontiers in Molecular Biosciences·Alexia Hervieu, Stéphanie Kermorgant
Jun 14, 2020·Cancer Discovery·Gonzalo RecondoMark M Awad
Aug 25, 2021·Journal of Hematology & Oncology·Leylah M DrusboskyChukwuemeka V Ikpeazu

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BETA
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FCS
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xenograft
xenografts
transgenic

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