Trametinib in metastatic melanoma

Chopra, Neha; Nathan, Paul

doi:10.1586/14737140.2015.1060127

Cited by 11 publications

(7 citation statements)

References 98 publications

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“…1a, b and 2a, b), and these phenomena also confirmed with trametinib, the only MEK inhibitor currently approved for the treatment of melanoma harboring a B-Raf mutation (Figs. 1c and 2c and Additional file 1: Figure S1C and D) [27]. Furthermore, the combined treatment also potentiated the effect of the HDAC inhibitor alone in BxPC-3 cells with wild type K-Ras (Figs.…”

Section: Resultsmentioning

confidence: 98%

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status

Chao

Chang

et al. 2019

Clin Epigenet

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Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo . Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Electronic supplementary material The online version of this article (10.1186/s13148-019-0681-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 98%

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status

Chao

Chang

et al. 2019

Clin Epigenet

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“…This finding can provide a rationale for yet another targeted therapy approach. Trametinib is a MEK1/2 inhibitor currently approved by the FDA for the treatment of BRAF-mutant melanoma (33), and another small molecule with a known safety profile in humans – pyrimethamine – has been identified recently as a potent STAT3 inhibitor (34,35). A combination of these two drugs could be used to more efficiently target some of the downstream mediators of IL-6 signaling, as well as prevent any compensatory activation of these pathways by other cytokines, such as RANTES or IL-8, which are also secreted in co-culture of tumor cells and CAFs (Fig.…”

Section: Discussionmentioning

confidence: 99%

IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment

et al. 2018

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The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers. These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. .

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“…Thus, compared to standard chemotherapy (Chapman et al, ), BRAF inhibitors could exhibit clinical benefits in ~ 29.1% (26/89) of our cohort bearing such mutations. Although resistance to such drugs inevitably develops, combination therapies, including dabrafenib and, the selective MEK inhibitor, trametinib (Chopra & Nathan, ; Robert, Karaszewska, et al, ), have recently been approved to treat patients following disease progression. Other BRAF mutations, however, were insensitive to known BRAF TKIs (Yao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling

Zou

Ou²,

Ren

et al. 2020

Pigment Cell Melanoma Res

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The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non‐cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture‐based next‐generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm‐level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non‐cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

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Trametinib in metastatic melanoma

Cited by 11 publications

References 98 publications

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status

IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment

Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling

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