Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinases catalyse key phosphorylation reactions in signalling cascades that affect every aspect of cell growth, differentiation and metabolism. The kinases have become prime targets for drug intervention in the diseased state, especially in cancer. There are currently 10 drugs that have been approved for clinical use and many more in clinical trials. This review summarises the structural basis for protein kinase inhibition and discusses the mode of action for each of the approved drugs in the light of structural results. All but one of the approved compounds target the ATP binding site on the kinase. Both the active and inactive conformations of protein kinases have been used in strategies to produce potent and selective compounds. Targeting the inactive conformation can give high specificity. Targeting the active conformation is favourable where the diseased state has arisen from activating mutations, but such inhibitors generally target several protein kinases. Drug resistance mutations are a potential risk for both conformational states, where drug-binding regions are not directly involved in catalysis. Imatinib (Glivec), the most successful of protein kinase inhibitors, targets the inactive conformation of ABL tyrosine kinase. Newer compounds, such as dasatinib, which targets the ABL active state, have been developed to increase potency and have proved effective for some, but not all, drug-resistant mutations. The first epidermal growth factor receptor (EGFR) inhibitors in clinical use [gefitinib (Iressa) and erlotinib (Tarceva)] targeted the active form of the kinase, and this proved advantageous for patients whose cancer was caused by mutations that resulted in a constitutively active EGFR kinase domain. Newer approved compounds, such as lapatinib (Tykerb), target the inactive conformation with high potency. A further compound that forms a covalent attachment to the kinase has been found to overcome one of the major drug resistance mutations, where the effectiveness of the drug in vivo is dependent on its ability to compete successfully in the presence of cellular concentrations of ATP. Inhibitors of vascular endothelial growth factor receptor (VEGFR) kinase against cancer angiogenesis show the advantage of some relaxation in specificity. Sorafenib, originally developed as RAF inhibitor, is now in clinical use as a VEGFR inhibitor. Temsirolimus (a derivative of rapamycin) is the only example of a drug in clinical use that does not target the kinase ATP site. Instead rapamycin, when in complex with the protein FKBP12, effectively targets mTOR kinase at a site located on a domain, the FRB domain, that appears to be involved in localisation or substrate docking.
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PMID:Protein kinase inhibitors: contributions from structure to clinical compounds. 1929 66

The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.
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PMID:mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). 1957 3

Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2-amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER-/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels.
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PMID:PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells. 2308 82