MEK Inhibitor TAK-733
About: MEK Inhibitor TAK-733 is a(n) research topic. Over the lifetime, 4 publication(s) have been published within this topic receiving 49 citation(s).
TL;DR: It is demonstrated that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest.
Abstract: The goal of this study was to investigate the activity of the selective MEK1/2 inhibitor TAK-733 in both melanoma cell lines and patient-derived melanoma xenograft models. In vitro cell proliferation assays using the sulforhodamine B assay were conducted to determine TAK-733 potency and melanoma responsiveness. In vivo murine modeling with eleven patient-derived melanoma explants evaluated daily dosing of TAK-733 at 25 or 10 mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo studies. TAK-733 demonstrated broad activity in most melanoma cell lines with relative resistance observed at IC50 > 0.1 μmol/L in vitro. TAK-733 also exhibited activity in 10 out of 11 patient-derived explants with tumor growth inhibition ranging from 0% to 100% (P < 0.001-0.03). Interestingly, BRAF(V600E) and NRAS mutational status did not correlate with responsiveness to TAK-733. Pharmacodynamically, pERK was suppressed in sensitive cell lines and tumor explants, confirming TAK-733-mediated inhibition of MEK1/2, although the demonstration of similar effects in the relatively resistant cell lines and tumor explants suggests that escape pathways are contributing to melanoma survival and proliferation. These data demonstrate that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest. Particularly interesting is the activity in BRAF wild-type models, where current approved therapy such as vemurafenib has been reported not to be active.
26 Feb 2016-Blood Cancer Journal
TL;DR: A TAK-733 inhibitor reduces proliferation, affects cell cycle and apoptosis, and synergizes with other targeted therapies in multiple myeloma.
Abstract: MEK inhibitor, TAK-733 reduces proliferation, affects cell cycle and apoptosis, and synergizes with other targeted therapies in multiple myeloma
02 Oct 2015-Oncotarget
TL;DR: The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies.
Abstract: // Christopher H. Lieu 1 , Peter J. Klauck 1 , Patrick K. Henthorn 1 , John J. Tentler 1 , Aik-Choon Tan 1 , Anna Spreafico 1 , Heather M. Selby 1 , Blair C. Britt 1 , Stacey M. Bagby 1 , John J. Arcaroli 1 , Wells A. Messersmith 1 , Todd M. Pitts 1 and S. Gail Eckhardt 1 1 Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Correspondence to: Christopher H. Lieu, email: // Keywords : MEK, colorectal cancer, patient derived xenografts, TAK-733 Received : August 09, 2015 Accepted : September 05, 2015 Published : October 01, 2015 Abstract Background: CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor. Materials and Methods: In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine B assay. Twenty patient-derived colorectal cancer xenografts were then treated with TAK-733 in vivo . Tumor growth inhibition index (TGII) was assessed to evaluate the sensitivity of the CRC explants to TAK-733 while linear regression was utilized to investigate the predictive effects of genotype on the TGII of explants. Results: Fifty-four CRC cell lines were exposed to TAK-733, while 42 cell lines were deemed sensitive across a broad range of mutations. Eighty-two percent of the cell lines within the sensitive subset were BRAF or KRAS/NRAS mutant, whereas 80% of the cell lines within the sensitive subset were PIK3CA WT. Twenty patient-derived human tumor CRC explants were then treated with TAK-733. In total, 15 primary human tumor explants were found to be sensitive to TAK-733 (TGII ≤ 20%), including 9 primary human tumor explants that exhibited tumor regression (TGII > 100%). Explants with a BRAF/KRAS/NRAS mutant and PIK3CA wild-type genotype demonstrated increased sensitivity to TAK-733 with a median TGII of -6%. MEK-response gene signatures also correlated with responsiveness to TAK-733 in KRAS-mutant CRC. Conclusions: The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants. While the preclinical activity observed in this study was considerable, single-agent efficacy in the clinic has been limited in CRC, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies.
27 May 2015-Annals of Nuclear Medicine
TL;DR: 18F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment and showed dose-dependent inhibition of tumor growth and 18F- FDG uptake in tumor tissue.
Abstract: Objective The aim of this study was to evaluate the potential of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.
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