title: Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression.
abstract: 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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Yori
authors.affiliation: Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lozada
authors.affiliation: Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Darcie D
authors.initials: DD
authors.lastname: Seachrist
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Fadi W
authors.initials: FW
authors.lastname: Abdul-Karim
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Christine N
authors.initials: CN
authors.lastname: Booth
authors.affiliation: Department of Radiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Biomedical Engineering, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.affiliation: Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Genetics and Division of General Medical Sciences-Oncology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. keri@case.edu.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Keri
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016391:Genes, src / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; C546842:MTOR protein, human; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000069439:Dasatinib; D020123:Sirolimus