Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25023728
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Cancer Res
2014[Sep]; 74
(17
): 4762-71
PMID25023728
show ga
Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer is often
mediated by activation of bypass pathways that sustain growth. Src and mammalian
target of rapamycin (mTOR) are two intrinsic targets that are downstream of most
RTKs. To date, limited clinical efficacy has been observed with either Src or
mTOR inhibitors when used as single agents. Resistance to mTOR inhibitors is
associated with loss of negative feedback regulation, resulting in
phosphorylation and activation of AKT. Herein, we describe a novel role for Src
in contributing to rapalog-induced AKT activation. We found that dual activation
of Src and the mTOR pathway occurs in nearly half of all breast cancers,
suggesting potential cross-talk. As expected, rapamycin inhibition of mTOR
results in feedback activation of AKT in breast cancer cell lines. Addition of
the Src/c-Abl inhibitor, dasatinib, completely blocks this feedback activation,
confirming convergence between Src and the mTOR pathway. Analysis in vivo
revealed that dual Src and mTOR inhibition is highly effective in two mouse
models of breast cancer. In a luminal disease model, combined dasatinib and
rapamycin is more effective at inducing regression than either single agent.
Furthermore, the combination of dasatinib and rapamycin delays tumor recurrence
following the cessation of treatment. In a model of human EGFR-2-positive
(HER2(+)) disease, dasatinib alone is ineffective, but potentiates the efficacy
of rapamycin. These data suggest that combining mTOR and Src inhibitors may
provide a new approach for treating multiple breast cancer subtypes that may
circumvent resistance to targeted RTK therapies.
free
free
free
