MEK inhibition in BRAF mutated melanoma

Rapamycin (also known as sirolimus or Rapamune, Wyeth) is the first described mTOR inhibitor [3]. This drug, originally developed as an antifungal agent, was soon found to have immunosuppressive and antineoplasmatic actions [4]. Systemic efforts to decipher the molecular mechanisms MEK inhibition of these actions led to the isolation of the mTOR protein and the identification of two multimolecular complexes that are formed bymTOR, namely, themTOR complex 1 (mTORC1) and 2 (mTORC2) . mTOR is the mammalian ortholog of a yeast serine-threonine kinase called target of rapamycin (TOR) [6]. Except for mTOR itself and the proteins mLST8/ GL [mammalian LST8 (lethal with SEC13 protein 8), also known as G protein beta subunit-like] and DEPTOR, which are common B-Raf inhibition in both mTORC1 and mTORC2, several different constitutional proteins associate to form the two mTOR complexes [7, 8].
These multipeptidic structures are situated inside a signaling network, the mTOR network, characterized by many feedback loops and crosslinks among its various components [9]. Activity of mTORC1 is regulated by multiple molecular pathways that conduct input generated by growth factors, hormones, cytokines, amino acids, energy, p38 MAPK activation stress- and oxygen- related signals [10?C13]. Among these cascades are the PI3K/Akt (Phosphoinositide 3-kinase/Akt) and Raf/MEK/ ERK (Raf/MEK/extracellular signal-regulated kinase) pathways, which are commonly activated in cancer and may cooperate in malignant transformation [9, 12]. Both pathways trigger the activity of mTORC1 through downregulation of the inhibitory effect of the TSC1-TSC2 (tuberous sclerosis complex 1-tuberous sclerosis complex 2) complex on Rheb (Ras homolog enriched in brain) protein [10, 12].
Akt kinase affects mTOR by way of two mechanisms. First, it lies upstream of mTORC1 and controls its activation. Second, Akt lies downstream of mTORC2 and depends on the latter as well as on PDK1 (pyruvate dehydrogenase kinase, isozyme 1) for full activation [7, 14]. Regulation of the two mTOR complexes bears some resemblance. For example, similarly to mTORC1, mTORC2 may also be activated by growth factors, hormones and amino acids, and this upregulationmay be PI3K mediated [7, 15, 16]. In contrast, the TSC1-TSC2 complex, which suppresses mTORC1 activity, may promote mTORC2 signaling [10].
mTORC2 regulates Akt, SGK1(serum- and glucocorticoidinduced protein kinase 1), and PKC (protein kinase C, alpha) phosphorylation and controls organization of actin cytoskeleton as well as JNK Signaling Pathway cell size, cell cycle progression, proliferation, and survival. The best characterized targets of mTORC1 are the S6 kinases [S6K1 (also known as p70S6) and S6K2] and the eukaryotic initiating factor-4e (eIF4e) binding proteins 1 and 2 (4E-BP1 and 4E-BP2) [9?C 11]. Upon activation, mTORC1 triggers vital anabolic processes such as ribosome biogenesis, cap-dependent transla tion, uptake of nutrients including glucose and amino acids, biosynthesis of amino acids, proteins, and lipids as well as (adenosine triphosphate) ATP sensing. Moreover, gene transcription, cell growth, cell cycle progression, proliferation, and survival are induced.
In addition, active mTORC1 downregulates macroautophagy and other catabolic processes such as fatty acid oxidation and protein degradation, while, in contrast, it ARQ 197 stimulates aerobic glycolysis Dysregulated activation of the mTORC1 pathway has been associated with tumor biology. Aberrant mTORC1 signaling disrupts homeostatic cell balance and contributes to uncontrolled proliferation and cell growth, survival, as well as angiogenesis and metastasis [9]. The same malignancyinducing processes may be also promoted by abnormally elevated mTORC2 signaling.

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S1008 Selumetinib (AZD6244) Selumetinib (AZD6244, ARRY-142886) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib suppresses cell proliferation, migration and trigger apoptosis. Phase 3.

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