Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

Background Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylino...

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Vydané v:	Cancer chemotherapy and pharmacology Ročník 71; číslo 4; s. 829 - 842
Hlavný autor:	Burris, Howard A.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Berlin/Heidelberg Springer-Verlag 01.04.2013 Springer Springer Nature B.V
Predmet:	Animals Antineoplastic agents Biological and medical sciences Breast Neoplasms - drug therapy Cancer Research Drug Resistance, Neoplasm Glioblastoma - drug therapy Gynecology. Andrology. Obstetrics Humans Lung Neoplasms - drug therapy Mammary gland diseases Medical sciences Medicine Medicine & Public Health Neoplasms - drug therapy Neurology Oncology Pharmacology. Drug treatments Pharmacology/Toxicology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - physiology Pneumology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - physiology Review Article Signal Transduction - drug effects TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - physiology Tumors Tumors of the nervous system. Phacomatoses Tumors of the respiratory system and mediastinum Resistance Sensitivity Breast cancer PI3K/AKT/mTOR pathway Lung cancer Glioblastoma Antineoplastic agent Breast disease Acquired Bronchopulmonary Malignant glioma Bronchus disease Lung disease Nervous system diseases Enzyme Respiratory disease Transferases Akt protein kinase Malignant tumor 1-Phosphatidylinositol 3-kinase Mammary gland diseases Treatment Central nervous system disease Mammalian target of rapamycin Cancer
ISSN:	0344-5704, 1432-0843, 1432-0843
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Shrnutí:	Background Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated. Methods PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations. Results Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation. Conclusion Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.
Bibliografia:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23
ISSN:	0344-5704 1432-0843 1432-0843
DOI:	10.1007/s00280-012-2043-3