Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels

Smalley, Keiran S.M.; Contractor, Rooha; Haass, Nikolas K.; Lee, John Tayu; Nathanson, Katherine L.; Medina, Calvo; Flaherty, Keith T.; Herlyn, Meenhard

doi:10.1038/sj.bjc.6603596

Cited by 91 publications

(96 citation statements)

References 10 publications

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“…SKN-AS, SKN-SH, SKN-Be2C, IMR-32, SH-EP, B16/F10, and SK-MEL-28 cell lines were purchased from American Type Culture Collection and maintained in Dulbecco's Modified Eagle Medium (DMEM) and 10% (volume for volume; v/v) FBS or Eagle's Minimum Essential Medium (EMEM) and 10% (v/v) FBS. The human melanoma cell lines C8161, 451Lu, WM164, WM35, WM793, and 1205Lu were grown as described (19,20). Pediatric tumor cell lines STS26T, S462, S462-TY, ST88-14, T265, CMTRL-100, A673, and CRL-11226 were maintained in DMEM with 10% (v/v) FBS and 1% (v/v) penicillin/streptomycin.…”

Section: Cells and Cell Culturementioning

confidence: 99%

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

et al. 2013

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The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. Cancer Res; 73(16); 5169-82. Ó2013 AACR.

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Section: Cells and Cell Culturementioning

confidence: 99%

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

et al. 2013

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“…The mutational status of WM35, WM793, 1205Lu, 451Lu, and SbCl2 was reported in ref. 23 and of C8161 in ref. 24.…”

Section: Methodsmentioning

confidence: 99%

The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel

Haass

Sproesser

Nguyen

et al. 2008

Clinical Cancer Research

210

170

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Purpose: Disseminated melanoma is highly therapy resistant. The finding that 66% of melanomas harbor the activating BRAF V600E mutation has raised expectations for targeting the Ras/RAF/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway in melanoma. This study addresses the anti-melanoma activity of the MEK inhibitor AZD6244 (ARRY-142886). Experimental Design: We recently have shown that growing melanoma cells as threedimensional collagen-implanted spheroids enhances resistance to the MEK inhibitor U0126. Here, we investigated the anti-melanoma activity of AZD6244 in two-dimensional cell culture, the three-dimensional spheroid model, and an in vivo model. Results: In two-dimensional cell culture, AZD6244 was cytostatic and reduced the growth of melanoma cells in a concentration-dependent fashion through the induction of G 1 -phase cell cycle arrest. In our three-dimensional spheroid model, the effects of AZD6244 were largely cytostatic and reversible, with drug washout leading to spheroid regrowth. Finally, 1205Lu cells were grown as tumor xenografts in severe combined immunodeficient mice. After tumor establishment, mice were dosed twice daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased phospho-ERK in the tumors and significantly suppressed tumor growth. The original tumors remained viable, suggesting that AZD6244 monotherapy was largely cytostatic, and not proapoptotic in this model. Further studies showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15 mg/kg) led to tumor regression, indicating the potential for MEK inhibitor/chemotherapy drug combinations. Conclusions: Inhibition of MEK is cytostatic as a monotherapy in melanoma, but cytotoxic when combined with docetaxel.

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“…Even among V600E BRAF melanoma cell lines, the degree of ERK inhibition in the setting of MEK inhibition does not correlate very well with the effect of MEK inhibitors on cell cycle arrest. 71 Thus, it is not clear that ERK activation is the most reliable biomarker of effective MEK inhibition, although it is the most commonly used in clinical trials. Whereas cell cycle inhibition commonly is observed, apoptosis infrequently is induced by these agents.…”

Section: Mek Inhibitorsmentioning

confidence: 99%

BRAF, a target in melanoma

Flaherty

McArthur

2010

Cancer

113

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The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations. Cancer 2010;116:4902-13. V C 2010 American Cancer Society.KEYWORDS: BRAF, melanoma, oncogene, kinase inhibitor, mutation.Therapy for advanced melanoma has progressed slowly over the past 3 decades, whereas significant advances have been made with the application of cytotoxic chemotherapy and, more recently, targeted therapies in other cancers. The application of cytotoxic chemotherapies that have disease-altering ability in other cancers has severe limits in melanoma. Chemotherapy does not convincingly improve upon the natural history of metastatic disease and has no role in the adjuvant setting. Cytokine therapy has a niche in both the adjuvant and metastatic settings but confers a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy. The identification of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. 1 BRAF BiologyRaf kinases are components of the mitogen-activated protein (MAP) k...

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Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels

Cited by 91 publications

References 10 publications

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel

BRAF, a target in melanoma

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