A Phase II, Open-Label, Randomized Study to Assess the Efficacy and Safety of AZD6244 (ARRY-142886) Versus Pemetrexed in Patients with Non-small Cell Lung Cancer Who Have Failed One or Two Prior Chemotherapeutic Regimens

Hainsworth, John D.; Cebotaru, C.; Kanarev, Vladimir; Ciuleanu, Tudor-Eliade; Damyanov, Danail; Stella, Phillip J.; Ganchev, H.; Pover, G.; Morris, Clive; Tzekova, Valentina

doi:10.1097/jto.0b013e3181e8b3a3

Cited by 144 publications

(98 citation statements)

References 21 publications

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“…AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. Previous studies have shown that the inhibition of MEK1/2 can induce apoptosis by inhibiting ERK-mediated B-cell lymphoma 2 phosphorylation and stabilization (16,17). Currently available MEK1/2 inhibitors have shown moderate single-agent activity in various tumors (18).…”

Section: Discussionmentioning

confidence: 99%

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

Li¹,

Chen²,

Jiang³

et al. 2015

Oncology Letters

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Abstract. With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC), acquired resistance has become a major clinical problem. A combination of different signaling pathway inhibitors is a promising strategy to overcome this. In the present study, the mitogen-activated protein kinase kinase 1/2 inhibitor, AZD6244, was used in combination with gefitinib to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib-resistant cells. The EGFR-TKI-sensitive PC-9 (mutant EGFR/wild-type K-Ras) and EGFR-TKI-resistant A549 (wild-type EGFR/mutant K-Ras) human NSCLC cell lines were treated with AZD6244 alone, gefitinib alone or the combination of the two drugs, and the effects were evaluated using cell proliferation assays, with alterations in signaling pathways analyzed by western blotting. It was found that the growth inhibitory effect of combination treatment with gefitinib and AZD6244 was greater than that of gefitinib alone in the EGFR-TKI-resistant A549 cells. Treatment of A549 cells with gefitinib alone reduced the expression level of the activated form of Akt, and the combination of the two drugs showed stronger inhibition of phosphorylated-Akt and phosphorylated-extracellular signal-regulated kinases. The data showed that the combination of AZD6244 and gefitinib exhibited dose-dependent synergism in gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of AZD6244 to enhance the efficacy of gefitinib in patients with EGFR-TKI-resistant NSCLC.

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Section: Discussionmentioning

confidence: 99%

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

Li¹,

Chen²,

Jiang³

et al. 2015

Oncology Letters

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“…[18][19][20][21][22][23] Further, AZD6244 is a noncompetitive MEK inhibitor with preclinical antitumor activity in solid tumor models including hepatocellular, colon, myeloma, thyroid, pancreatic, melanoma, and breast cancers 19,20,41 and tested clinically in phase 1 24 and phase 2 trials of advanced, refractory colorectal, melanoma, and lung cancer. [25][26][27] AZD6244 has been examined in leukemia and myeloma models, [42][43][44] however to our knowledge, has never been tested in lymphoma.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK small molecule antagonist, AZD6244, in lymphoma cell lines, primary cells, and an in vivo human DLBCL xenograft model.…”

mentioning

confidence: 99%

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for nearly 35% of all non-Hodgkin lymphomas (NHL). Significant advances have been in the treatment of DLBCL, particularly with immunochemotherapy, however approximately 30%-40% of patients still die from this malignancy. In addition, short-and long-term toxicities of chemotherapy, including secondary malignancies and leukemias, continue to adversely impact the long-term prognosis of patients. Continued investigations of novel targeted therapeutic agents in DLBCL are warranted.The RAS/RAF/mitogen-activated protein kinase 1/2 (MEK1/2)/ extracellular signal-regulated kinase 1/2 (ERK1/2) plays a prominent role in cancer biology, including hematologic malignancies, in part through the regulation of cell growth and proliferation. [1][2][3][4][5] Activating mutations in RAS and RAF lead to aberrant activation of their downstream target, MEK1/2. Directly downstream of MEK1/2, ERK1 and ERK2 are intimately involved in transducing signals from growth factor receptors and cytokine receptors after ligand binding. 2 Furthermore, ERK is the only known catalytic substrate of MEK. 6 We and others have shown that the MEK/ERK signaling pathway is constitutively active in a large number of cancers, including hematologic malignancies. 3,4,[7][8][9] Moreover, the MEK/ERK signal transduction cascade has been shown to be susceptible to pharmacologic intervention. Thus, MEK has emerged as an attractive therapeutic target in cancer.The majority of preclinical, and especially clinical trial data studying MEK inhibitors to date have emerged largely from solid tumor studies. [10][11][12][13][14] We recently showed in preclinical studies that inhibition of ERK1/2 phosphorylation by 1st generation MEK and ERK inhibitors correlated with significant cell death in a lymphoma tumor model, 15 while others showed that sublethal concentrations of a 1st generation MEK antagonist potentiated the effect of sorafemib in lymphoma cells. 16 Furthermore, we recently demonstrated that MCT-1, an oncogene directly downstream of MEK/ ERK, is over-expressed in the majority of primary DLBCLs. 15 MCT-1 is known to colocalize with ERK1/2, while phosphorylation of MCT-1 protein by ERK is critical for stabilization of MCT-1 protein and for its functional ability to promote cell proliferation. 15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK sma...

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“…Ihle and colleagues reported that patients with NSCLC whose tumors had either KRAS-G12C or KRAS-G12V mutations had worse progression-free survival (PFS) compared with patients whose tumors had other KRASmutant tumors or lacked KRAS mutations (17). In lung cancer, a randomized phase II study evaluated selumetinib or pemetrexed in previously treated NSCLC, and demonstrated that the PFS in the selumetinib group was equivalent to that in the pemetrexed group, although this was a study of unselected patients with NSCLC (37). In contrast, a small study also examined the efficacy of selumetinib specifically in KRAS-mutant NSCLC, but demonstrated no responses (38).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Okumura¹

2014

Clinical Cancer Research

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Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G 1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.

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A Phase II, Open-Label, Randomized Study to Assess the Efficacy and Safety of AZD6244 (ARRY-142886) Versus Pemetrexed in Patients with Non-small Cell Lung Cancer Who Have Failed One or Two Prior Chemotherapeutic Regimens

Cited by 144 publications

References 21 publications

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

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