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Lori S Hart, JulieAnn Rader, Pichai Raman, Vandana Batra, Michael R Russell, Matthew Tsang, Maria Gagliardi, Lucy Chen, Daniel Martinez, Yimei Li, Andrew Wood, Sunkyu Kim, Sudha Parasuraman, Scott Delach, Kristina A Cole, Shiva Krupa, Markus Boehm, Malte Peters, Giordano Caponigro, John M Maris
PURPOSE: Neuroblastoma is treated with aggressive multi-modal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. EXPERIMENTAL DESIGN: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib...
October 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bernardo Queralt, Elisabet Cuyàs, Joaquim Bosch-Barrera, Anna Massaguer, Rafael de Llorens, Begoña Martin-Castillo, Joan Brunet, Ramon Salazar, Javier A Menendez
KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth...
September 12, 2016: Oncotarget
U Urner-Bloch, M Urner, N Jaberg-Bentele, A L Frauchiger, R Dummer, S M Goldinger
BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy...
September 2016: European Journal of Cancer
Marissa L Weber, Michelle C Liang, Keith T Flaherty, Jeffrey S Heier
IMPORTANCE: The use of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors has become more common in the treatment of systemic cancer. These agents have been associated with a central serous-like retinopathy in some patients. Recognition of such retinal findings and the relatively benign nature of these events is important to avoid unnecessary intervention, including the cessation of a potentially life-prolonging medication. OBJECTIVES: To evaluate the presence and characteristics of subretinal fluid (SRF) associated with the use of MEK inhibitors in the treatment of systemic cancer and to correlate the presence of SRF with visual acuity and symptoms over time...
August 1, 2016: JAMA Ophthalmology
Elon H C van Dijk, Danique E M Duits, Mieke Versluis, Gregrorius P M Luyten, Arthur A B Bergen, Ellen W Kapiteijn, Mark J de Lange, Camiel J F Boon, Pieter A van der Velden
Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation...
May 2016: Medicine (Baltimore)
K Watanabe, S Otsu, Y Hirashima, R Morinaga, K Nishikawa, Y Hisamatsu, T Shimokata, M Inada-Inoue, T Shibata, H Takeuchi, T Watanabe, K Tokushige, H Maacke, K Shiaro, Y Ando
PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID)...
June 2016: Cancer Chemotherapy and Pharmacology
Sarah E Woodfield, Linna Zhang, Kathleen A Scorsone, Yin Liu, Peter E Zage
BACKGROUND: Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models. METHODS: Levels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays...
2016: BMC Cancer
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