Basis For Targeting Met Activation Mediated Resistance to Pi3K Inhibition In Breast Cancer

<p>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 <strong>concurrent aberrations </strong>in <em>PI3K</em> and <em>MET</em> 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.</p> <p>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.(<a href="http://digitalcommons.library.tmc.edu/cgi/ir_submit.cgi#_ENREF_1" title="Raghav, 2012 #16">1</a>) We also analyzed DNA from 971 FFPE early breast tumors, and showed that <em>MET</em> and <em>PIK3CA</em> are frequently co-amplified, and a high copy number of either gene is associated with poorer prognostic features and the triple negative disease.(<a href="http://digitalcommons.library.tmc.edu/cgi/ir_submit.cgi#_ENREF_2" title="Gonzalez-Angulo, 2013 #17">2</a>) 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 <em>PIK3CA</em> 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 <em>MET</em> and <em>PIK3CA</em> 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.</p> <p>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 <em>MET</em> gene copy number, its distribution by tumor subtype, and correlation with patient outcome.(<a href="http://digitalcommons.library.tmc.edu/cgi/ir_submit.cgi#_ENREF_2" title="Gonzalez-Angulo, 2013 #17">2</a>) Our study is also unique for showing that the presence of <em>MET</em> aberrations enhances the tumorigenic effects induced by the <em>PIK3CA</em> mutations in breast cancer/epithelial cells; results from our tumor xenograft models corroborate with these <em>in vitro</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Gonzalez-Angulo, Ana M

Contributors dc:contributor

• Gordon B. Mills
• Lajos Pusztai
• Faye M. Johnson

• PI3K
• MET
• Therapy resistance
• Breast Cancer
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/418

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1443