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

Molecular Cancer

Research

Daniel Matthias Aebersold¹  Michaela Poliaková¹  Paola Francica¹  Michaela Medová¹  Yitzhak Zimmer¹  Lluís Nisa²  Roland Giger³  Pascal Häfliger⁴  Roch-Philippe Charles⁴ 

[1] Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3008, Bern, Switzerland;Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010, Bern, Switzerland;Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, 3008, Bern, Switzerland;Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010, Bern, Switzerland;Department of Otorhinolaryngology – Head and Neck Surgery, Inselspital, Bern University Hospital, and University of Bern, 3010, Bern, Switzerland;Department of Otorhinolaryngology – Head and Neck Surgery, Inselspital, Bern University Hospital, and University of Bern, 3010, Bern, Switzerland;Institute of Biochemistry and Molecular Medicine, University of Bern, 3012, Bern, Switzerland;

关键词: MET receptor tyrosine kinase;    PI3K pathway;    PIK3CA;    Resistance mechanisms;    Head and neck cancer;   

DOI  :  10.1186/s12943-017-0660-5

 received in 2016-11-10, accepted in 2017-05-10,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsMET 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.ResultsPIK3CAE545K 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.ConclusionsPIK3CA 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.

【 授权许可】

CC BY   
© The Author(s). 2017