Deregulation of the phosphatidylinositide 3-kinase(PI3K) and mammalian target of rapamycin(mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a major driving force in tumorigenesis.Thus,...Deregulation of the phosphatidylinositide 3-kinase(PI3K) and mammalian target of rapamycin(mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a major driving force in tumorigenesis.Thus,small molecules targeting this pathway are under active development as anticancer therapeutics.Although small-molecule inhibitors of the PI3K-mTOR pathway have shown promising clinical efficacy against human cancers,the emergence of drug resistance may limit their success in the clinic.To date,several resistance mechanisms,including both PI3K-dependent and-independent mechanisms,have been described.Here,we summarize the current understanding of resistance mechanisms to PI3K-mTOR inhibitors and discuss potential strategies for overcoming resistance for potential clinical application.展开更多
Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and...Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments.The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.展开更多
文摘Deregulation of the phosphatidylinositide 3-kinase(PI3K) and mammalian target of rapamycin(mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a major driving force in tumorigenesis.Thus,small molecules targeting this pathway are under active development as anticancer therapeutics.Although small-molecule inhibitors of the PI3K-mTOR pathway have shown promising clinical efficacy against human cancers,the emergence of drug resistance may limit their success in the clinic.To date,several resistance mechanisms,including both PI3K-dependent and-independent mechanisms,have been described.Here,we summarize the current understanding of resistance mechanisms to PI3K-mTOR inhibitors and discuss potential strategies for overcoming resistance for potential clinical application.
基金Supported by Ricerca Sanitaria LILT 2015Beneficentia Foundation Stiftung,No.BEN2016/16 grants
文摘Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments.The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.
