Selumetinib

1 . Holt SV, Logié A, Odedra R, Heier A, Heaton SP, Alferez D, Davies BR, Wilkinson RW, Smith PD.The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.Br J Cancer. 2012 Feb 28;106(5):858-66.
Abstract
BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations.

2 . Patel SP, Kim KB.Selumetinib (AZD6244; ARRY-142886) in the treatment of metastatic melanoma.Expert Opin Investig Drugs. 2012 Apr;21(4):531-9. Epub 2012 Mar 7.
Abstract
INTRODUCTION: Melanoma is the fifth most common cancer in men and seventh most common in women in the USA, and prognosis for patients with advanced melanoma is poor. The mitogen-activated protein (MAP) kinase signaling pathway is essential for proliferation and survival of melanoma cells. Effective inhibition of MAP kinase kinase (MEK) protein has been shown to downregulate the MAP kinase pathway, resulting in melanoma cell growth arrest and apoptosis. Selumetinib is an orally available, selective non-ATP-competitive MEK1 and MEK2 inhibitor. AREAS COVERED: In this review, the authors discuss the rationale for MEK inhibition therapy in melanoma and summarize data from the preclinical and clinical studies of selumetinib for advanced melanoma. EXPERT OPINION: As a majority of advanced melanomas have an activated MAP kinase signal transduction pathway, there is a strong preclinical rationale for investigating selumetinib in patients with metastatic melanoma. The results of early clinical studies of selumetinib suggest that selumetinib may have a role in melanoma therapy, especially in certain subsets of patients, such as those whose tumor harbors a BRAF mutation. Current studies of selumetinib are addressing the efficacy of selumetinib in these patients.

3 . Ma BB, Lui VW, Cheung CS, Lau CP, Ho K, Hui EP, Tsui SK, Ng MH, Cheng SH, Ng PK, Tsao SW, Chan AT.Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines.Invest New Drugs. 2012 May 8.
Abstract
This study evaluated the preclinical activity of selumetinib (AZD6244, ARRY-142866), an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK1/2) in 6 nasopharyngeal cancer (NPC) cell lines. Selumetinib could achieve up to 90 % inhibition of cell growth with the respective IC(50) values in NPC cell lines as follow: HK1?=?0.04 μM, HK1-LMP1(B95.8)?=?0.17 μM, HONE-1-EBV?=?0.46 μM, HONE-1?=?1.79 μM, CNE-2?=?2.20 μM and C666-1?>?10 μM. The drug-sensitive cell lines HK1, HK1-LMP1(B95.8) and HONE-1-EBV have higher basal expression of phosphorylated (pi)-MAPK than the less sensitive cell lines. BRAF mutations were not detected in all 6 cell lines. Re-introduction of the EBV genome into HONE-1 cells, generating the HONE-1-EBV cell line, seemed to result in elevated expression of pi-MAPK and sensitivity to selumetinib when compared with the parental HONE-1 cells. At a concentration of 0.5 μM and 5 μM, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G(0)/G(1) cycle arrest in HONE-1-EBV and HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and the EGFR tyrosine kinase inhibitor, gefitinib (at concentrations of 0.1, 3 and 9 μM) resulted in synergistic growth inhibition in HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and cisplatin (at concentrations of 0.1, 0.4, 0.8 and 2 μM) resulted in synergistic growth inhibition in HONE-1 and HONE-1-EBV cells. This result suggests that selumetinib alone or in combination with gefitinib or cisplatin maybe a promising strategy against NPC. Further studies are warranted.

4 . Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, Vaughn CS, Lorusso PM, Cohen RB, Davies MA, Kim KB.Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.Cancer. 2012 Sep 12.
Abstract
BACKGROUND: The high prevalence of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma v-ras oncogene homolog (NRAS) mutations in melanoma provides a strong rationale to test the clinical efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in this disease. The authors hypothesized that the presence of BRAF or NRAS mutations would correlate with clinical benefit among patients who received treatment with combination regimens that included the MEK inhibitor selumetinib. METHODS: BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib). The clinical response rate and the time to progression (TTP) were assessed as a function of BRAF and NRAS mutation status...

5 . Yang, Shu; AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. Molecular Cancer Therapeutics (2009), 8(9), 2537-2545.
Abstract
Gastric cancer is a deadly disease for which current therapeutic options are extremely limited. Vascular endothelial growth factor receptors and platelet-derived growth factor receptors regulate gastric cancer cell proliferation, invasion, and tumor angiogenesis. In the present study, we report that sorafenib therapy effectively inhibited tumor growth and angiogenesis in tumor xenografts. These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet-derived growth factor receptor-beta Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27. Sorafenib treatment also caused up-regulation of p-c-Raf Ser338 and p-extracellular signal-regulated kinase (ERK) Thr202/Tyr204 in gastric cancer xenografts. ...