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

The multidrug resistance gene 1 (MDR1) product, P-glycoprotein (P-gp), pumps out a variety of anticancer agents from the cell, including anthracyclines, Vinca alkaloids, and taxanes. The expression of P-gp therefore confers resistance to these anticancer agents. In our present study, we found that FTI-277 (a farnesyltransferase inhibitor), U0126 [an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)], and 17-allylamino-17-demethoxygeldanamycin (an inhibitor of heat shock protein 90) reduced the endogenous expression levels of P-gp in the human colorectal cancer cells, HCT-15 and SW620-14. In contrast, inhibitors of phosphatidylinositol 3-OH kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinase, and c-Jun NH(2)-terminal kinase did not affect P-gp expression in these cells. We further found that U0126 down-regulated exogenous P-gp expression in the MDR1-transduced human breast cancer cells, MCF-7/MDR and MDA-MB-231/MDR. However, the MDR1 mRNA levels in these cells were unaffected by this treatment. PD98059 (a MEK inhibitor), ERK small interfering RNA, and p90 ribosomal S6 kinase (RSK) small interfering RNA also suppressed P-gp expression. Conversely, epidermal growth factor and basic fibroblast growth factor enhanced P-gp expression, but the MDR1 mRNA levels were unchanged in epidermal growth factor-stimulated cells. Pulse-chase analysis revealed that U0126 promoted P-gp degradation but did not affect the biosynthesis of this gene product. The pretreatment of cells with U0126 enhanced the paclitaxel-induced cleavage of poly(ADP-ribose) polymerase and paclitaxel sensitivity. Furthermore, U0126-treated cells showed high levels of rhodamine123 uptake. Hence, our present data show that inhibition of the MEK-ERK-RSK pathway down-regulates P-gp expression levels and diminishes the cellular multidrug resistance.
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PMID:Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. 1762 Apr 38

Lonafarnib is an orally bioavailable farnesyltransferase inhibitor. Originally developed to block the membrane localization of Ras, subsequent work suggested that farnesyltransferase inhibitors mediate their antitumor activities by altering the biological activities of additional farnesylated proteins. Breast tumor models that express wild-type Ras have been shown to be sensitive to farnesyltransferase inhibitors. We have determined the effects of combining lonafarnib with the antiestrogen 4-hydroxy tamoxifen on hormone-dependent breast cancer cell lines in vitro. The effects of combining lonafarnib with tamoxifen or the aromatase inhibitor anastrozole on the growth of two different MCF-7 breast tumor xenograft models were also evaluated. In four of five human breast cancer cell lines, lonafarnib enhanced the antiproliferative effects of 4-hydroxy tamoxifen. The combination prevented MCF-7 cells from transitioning through the G1 to S phase of the cell cycle and augmented apoptosis. This was associated with reduced expression of E2F-1 and a reduction in hyperphosphorylated retinoblastoma protein. Lonafarnib plus 4-hydroxy tamoxifen also inhibited the mammalian target of rapamycin signal transduction pathway. In nude mice bearing parental MCF-7 or aromatase-transfected MCF-7Ca breast tumor xenografts, lonafarnib enhanced the antitumor activity of both tamoxifen and anastrozole. These studies indicate that lonafarnib enhances the efficacy of endocrine agents clinically used for treating hormone-dependent breast cancer.
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PMID:Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336). 1766 98

High-grade primary brain tumors remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of these malignant tumors and identify oncogenic pathways that might be amenable to small-molecule and antibody 'targeted' therapy. Growth factor signaling pathways are often upregulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include Raf, MEK, PI3K, Akt (protein kinase B), and mTOR (mammalian target of rapamycin). In addition, overactivity of VEGF and other effectors leads to neoplastic angiogenesis. 'Targeted' therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (eg, imatinib and erlotinib) and farnesyltransferase inhibitors (eg, tipifarnib). Molecular therapeutic small molecules specific to Raf, PI3K, and mTOR include sorafenib, LY-294002, and temsirolimus, respectively. 'Targeted' anti-angiogenesis approaches include mAbs to VEGF (eg, bevacizumab) and VEGF receptor tyrosine kinase inhibitors (eg, vatalanib and sunitinib). Further development of 'targeted' therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality-of-life for patients with malignant brain tumors.
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PMID:Small-molecule and antibody approaches to molecular chemotherapy of primary brain tumors. 1805 72

Growth, survival and differentiation of hematopoietic cells are regulated by the interactions between hematopoietic growth factors and their receptors. The defect in these interactions results in a failure of hematopoiesis, while aberrantly elevated and/or sustained activation of these signals cause hematologic malignancies. Among them, constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c-Kit, platelet-derived growth factor receptor (PDGFR) and FLT3, are often involved in the pathogenesis of various types of hematologic malignancies. Constitutive activation of RTKs is provoked by several mechanisms including chromosomal translocations and various mutations involving their regulatory regions. Chromosomal translocations commonly generate chimeric proteins consisting of the cytoplasmic domain of RTKs and the dimerization or multimerization motif of the fusion partner, resulting in the constitutive dimerization of RTKs. On the other hand, missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop, and extracellular domain, also cause constitutive activation of RTKs mainly by preventing the auto-inhibitory regulation. Oncogenic RTKs activate downstream signaling molecules such as Ras/MAPK, PI3-K/Akt/mTOR, and STATs as well as ligand-activated wild type RTKs. However, their signals are quantitatively and qualitatively different from wild type RTKs. Based on these findings, several agents that target oncogenic RTKs or their downstream molecules have been developed: imatinib and FLT3 inhibitors for RTKs themselves, farnesyltransferase inhibitors, mTOR inhibitors and MEK inhibitors for the downstream signaling molecules. As promising results have been obtained in several clinical trials using these agents, the establishment of these molecular targeted agents is expected.
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PMID:Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies. 1817 85

Effective treatment of glioblastoma multiforme (GBM) is complicated by multiple factors, including the diffusely infiltrative nature of the disease, which limits complete surgical resection; the difficulty in overcoming the blood-brain barrier with systemic therapies; and the challenge of identifying novel means of treating the residual hypoxic tumor cells that are relatively resistant to radiotherapy (RT) and chemotherapy. Clear survival advantages have been demonstrated with postresection RT to doses of 5,000-6,000 cGy, but further attempts at dose escalation over 6,000 cGy have resulted in increased toxicity without a survival benefit. In an effort to improve local control of tumor and limit toxicity to normal brain tissue, novel imaging techniques (eg, chemical shift imaging) are being explored in order to better define RT fields. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but have undefined roles outside of clinical trials in treating newly diagnosed GBM. Stereotactic RT may have a survival advantage in subgroups that have undergone a gross total resection and have favorable (recursive partitioning analysis class IV) disease. In contrast, experience with hyperfractionated RT in GBM has shown that survival outcomes may actually be unfavorable in certain patient subgroups. Novel means of delivering RT, including radioimmunotherapy, have demonstrated efficacy with acceptable toxicity. Systemic agents are being explored as potential radiosensitizers, with the recent emergence of temozolomide as a model radiosensitizing agent having a positive impact on survival. Ongoing investigations are evaluating temozolomide in combination with other systemic agents, and additional agents (eg, motexafin gadolinium, mammalian target of rapamycin inhibitors, farnesyltransferase inhibitors) have shown promising activity in combination with RT.
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PMID:Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. 1818 89

The EGF-receptor (EGFR) and downstream signaling molecules have emerged as promising targets for inhibition by small molecules in the treatment of nonsmall cell lung cancer (NSCLC). In this study expression of pivotal signaling molecules in the EGFR pathway were used to predict response to inhibitors of the EGFR signaling cascade. NSCLC cell lines were treated with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and PD16,8393, the AKT inhibitor SH-6 and LY294002, the farnesyltransferase inhibitor L744832, and the mTOR inhibitor rapamycin. Response was correlated to expression of AKT, p-AKT, EGFR, S6K1, p-S6K1, PTEN and to the mutation status of EGFR and KRAS. As expected, mutation of the EGFR predicted response to EGFR-TKI. The resistance mutation T790M conferred resistance to treatment with gefitinib, but not to the irreversible EGFR inhibitor PD16,8393. In cell lines independent of the EGFR, expression of PTEN correlated with resistance to AKT inhibition, EGFR expression correlated to resistance to 17-AAG and L744832 and S6K1 as well as p-S6K1 expression correlated with sensitivity to rapamycin.
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PMID:Expression of signaling mediators downstream of EGF-receptor predict sensitivity to small molecule inhibitors directed against the EGF-receptor pathway. 1830 39

Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We therefore investigated the mechanisms mediating resistance to the therapeutic activities of SCH66336 in HNSCC and NSCLC. Our various analyses showed that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of SCH66336 in HNSCC and NSCLC cells. Treatment with SCH66336 activated the IGF-IR/phosphatidylinositol 3-kinase/Akt pathway, leading to increased mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin in a subset of HNSCC and NSCLC cell lines that were insensitive to the apoptotic activities of the drug. Inhibition of IGF-IR, Akt, or mTOR or the knockdown of survivin expression abolished resistance to SCH66336 and induced apoptosis in the cells. Overexpression of survivin by the use of adenoviral vector protected SCH66336-sensitive HNSCC cells from the apoptotic activities of the drug. Our results suggest that expression of phosphorylated IGF-IR, phosphorylated Akt, phosphorylated mTOR, and survivin serves as biological markers of SCH66336 responsiveness in HNSCC and NSCLC cells and that SCH66336 induces survivin expression through an IGF-IR/Akt/mTOR-dependent pathway. Thus, combining inhibitors of IGF-IR, phosphatidylinositol 3-kinase/Akt, mTOR, or survivin with SCH66336 may be an effective anticancer therapeutic strategy for patients with HNSCC or NSCLC.
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PMID:Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. 1831 83

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies. In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
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PMID:Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. 1834 18

The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer.
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PMID:Tumorigenic activity and therapeutic inhibition of Rheb GTPase. 1870 78

The mechanisms of action of farnesyltransferase inhibitors (FTIs) involve Rheb and the phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. mTOR in particular plays a key role in the regulation of autophagy. Collectively, the literature suggests that FTIs very likely induce autophagy, but thus far there have been no reports that FTIs affect this process relevant to cancer cell biology. We hypothesized that FTIs can induce autophagy. In this study, we found that the FTIs manumycin A, FTI-276, and lonafarnib induced autophagy in two human cancer cell lines. We also found that neither inhibition of apoptosis with a pan-caspase inhibitor nor inhibition of autophagy increased the number of clones of lonafarnib-treated U2OS osteosarcoma cells that formed in soft agar. Although whether autophagy is a cell death or cell survival mechanism after FTI treatment remains unresolved, our data show that cancer cells apparently can shift between apoptosis and autophagy once they are committed to die after FTI treatment.
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PMID:Autophagy induced by farnesyltransferase inhibitors in cancer cells. 1876 23


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