Date of Graduation
Doctor of Philosophy (PhD)
Gordon B. Mills
Faye M. Johnson
Naoto T. Ueno
Melissa L. Bondy
The identification of resistance mechanisms to emerging therapies, such as those targeting the PI3K pathway and the MET receptor, has the potential to benefit a significant number of patients with breast cancer. In this study we hypothesized that concurrent aberrations in PI3K and MET will render breast cancers resistant to therapies targeting each pathway, and that combination therapy targeting the PI3K and MET pathway will optimize therapy-effect by preventing the acquisition of resistance.
We analyzed cMET and phospho-cMET levels in 257 breast cancer samples and found that high levels of both the proteins were seen in all breast cancer subtypes, which correlated with poor prognosis.(1) We also analyzed DNA from 971 FFPE early breast tumors, and showed that MET and PIK3CA are frequently co-amplified, and a high copy number of either gene is associated with poorer prognostic features and the triple negative disease.(2) Additionally, we determined the effect of MET-T1010I, MET-Y1253D and MET overexpression, found in breast cancers, on the activity of the two most common breast cancer PIK3CA mutations (E545K and H1047R), in a model of breast epithelial cells (MCF-10A) and a cell line breast cancer model (HCC1954). Our results suggest that tumors with concurrent aberrations in MET and PIK3CA are likely to be more aggressive and resistant to therapies targeting each pathway, and that combinatorial therapy (with MET and PI3K pathway inhibitors) could circumvent this resistance.
This is the first study to investigate the significance of differential expression of cMET and p-cMET in different breast cancer subtypes, to report p-cMET levels as a prognostic factor in breast cancer, and also, the first to report MET gene copy number, its distribution by tumor subtype, and correlation with patient outcome.(2) Our study is also unique for showing that the presence of MET aberrations enhances the tumorigenic effects induced by the PIK3CA mutations in breast cancer/epithelial cells; results from our tumor xenograft models corroborate with these in vitro findings. Moreover, we are the first to provide evidence for the potential activity of combinatorial therapy using MET and PI3K pathway inhibitors against breast cancer.
PI3K, MET, Therapy resistance, Breast Cancer