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

Abstract

Background

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.

Methods

MET and/or PI3K pathway inhibition was assessed in NIH3T3 cells harboring MET-activating point mutation with or without ectopic expression of PIK3CA^E545K and PIK3CA^H1047R, 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.

Results

PIK3CA^E545K and PIK3CA^H1047R confer resistance to MET inhibition in MET-driven models. PIK3CA^H1047R was more potent than PIK3CA^E545K 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 PIK3CA^H1047R. In head and neck cancer cells the combination of MET/PI3K inhibitors led to more-than-additive effects.

Conclusions

PIK3CA mutations can lead to resistance to MET inhibition, supporting future clinical evaluation of combinations of PI3K and MET inhibitors in common scenarios of malignant neoplasms featuring aberrant MET expression and PIK3CA mutations.

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