Targeting endocrine resistance: is there a role for mTOR inhibition?
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a critical intracellular signaling cascade that mediates both growth factor-induced proliferation and cell survival with deregulated signaling through this pathway, a feature of most cancers. Here, we review the role of the PI3K/Akt/mTOR pathway in endocrine-resistant breast cancer and discuss preclinical and clinical studies combining endocrine therapy with mTOR inhibition. Key to the success of such an approach will be a clinical trial design incorporating appropriate tumor selection and validation of biomarkers predicting benefit. Ultimately, a greater understanding of the biology and compensatory mechanisms will allow the partnering of key signal transduction inhibitors together to provide maximal "vertical" or "horizontal" blockade with further preclinical and clinical studies planned to examine possible synergistic combinations with endocrine therapy.
Breast Unit, Royal Marsden Hospital, 123 Old Brompton Road, London, United Kingdom. amna.sheri@icr.ac.uk
Amna
A
Sheri
Lesley-Ann
LA
Martin
Stephen
S
Johnston
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases