Sorafenib (BAY 43‐9006, Nexavar®), a Dual‐Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature

Adnane, Lila; Trail, Pamela A.; Taylor, Ian; Wilhelm, Scott M.

doi:10.1016/s0076-6879(05)07047-3

Cited by 415 publications

(284 citation statements)

References 28 publications

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“…2 is the fifth most common cancer and the third leading cause of cancer death worldwide (1). Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation, and thus remains one of the most difficult cancers to treat (2).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

“…Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation, and thus remains one of the most difficult cancers to treat (2). Sorafenib, a multi-targeted receptor tyrosine kinase (RTK) inhibitor that targets the Raf kinases and other kinases such as VEGFR1-3, PDGFR-␤, FLT-3, and c-kit (1,(3)(4) has shown survival benefits in patients with advanced HCC and was approved for use in HCC by the United States Food and Drug Administration in 2007 (5-7). However, sorafenib only provides a modest effect, prolonging survival in patients with HCC from a median 7.9 to 10.7 months.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

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Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Lin

Tai³

et al. 2013

Journal of Biological Chemistry

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Background: Nilotinib, an approved drug for leukemia, has been investigated in HCC. Results: Nilotinib induced autophagy in HCC cell lines, including PLC5, Huh-7, and Hep3B. Conclusion: Nilotinib-induced AMPK activation and subsequent autophagy is a major mode of action of nilotinib in HCC. Significance: Elucidating the mechanisms by which nilotinib works on HCC is fundamental to develop the new treatment for HCC.

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Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Lin

Tai³

et al. 2013

Journal of Biological Chemistry

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“…In many cancers, both the overexpression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain, contribute to constitutive signaling; thus, these receptors make attractive targets for targeted therapies [80]. For example, in the transition from radial to vertical growth phase, melanoma as well as angiogenesis is heralded by both the expression and release of vascular endothelial growth factor (VEGF), which facilitates both growth of new blood and the tumor [29,81,82]; inhibition of VEGF receptor (VEGFR) by sorafenib (formally known as BAY 43-9006 [83,84] in combination with antibodies that block VEGF such as bevacizumab might represent important combination therapy in metastatic melanoma patients. Early clinical development of sorafenib given with carboplatin and paclitaxel to patients with relapsed, refractory metastatic melanoma shows striking activity with prolonged progression-free survival (PFS; median PFS, 10 months) [85,86].…”

Section: C-kit (Cd117)mentioning

confidence: 99%

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Carlson

Linette

Aplin

et al. 2007

Dermatologic Clinics

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Melanocytes are an intraepidermal population of dendritic cells responsible for the production of melanin, a pigment that varies from yellow to brown to black pigment that after transfer to neighboring keratinocytes acts both as an endogenous screen and a buffering system against harmful ultraviolet (UV) wavelengths in sunlight [1]. Skin pigmentation has both individual and societal implications. The cosmetic desire for increased pigmentation (tanning) has resulted in many deleterious alterations including hastened skin ageing with wrinkles and poikiloderma and an increase in lentigines, melanocytic nevi, and melanoma. Focal or widespread loss of normal pigmentation not only renders individuals extraordinarily vulnerable to the harmful effects of sunlight (eg, increased risk of skin cancer in albinism), but it can also result in severe emotional stress and, in some societies, ostracism and discrimination (eg, vitiligo).Melanocytes are derived from the neural crest and are located along the basal layer of the epidermis and within the hair follicle, predominately the basal layer of the hair bulb matrix [1,2]. By the 50th day of intrauterine life, melanocytes can be detected in the epidermis; their migration to the epidermis and survival is dependent on receptor tyrosine kinase (RTK) c-Kit and its ligand stem cell factor (SCF) within the epidermis [3,4]. Mutations of the c-Kit gene lead to patches of hypopigmentation caused by lack of melanocyte migration, termed piebaldism [5]. Another important signaling molecule in melanocyte migration and development is Wnt5a, which signals via the Frizzled-5 receptor [6]. Overexpression of Wnt5a/ Frizzled is found in melanomas and associated with increased cell motility and invasiveness [7,8].Skin keratinocytes obtain melanin pigment from melanocytes, and keratinocytes provide the necessary microenvironment for melanocyte survival, proliferation, differentiation, and migration via production of ligands that interact with melanocyte receptors [1,[9][10][11] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript epidermal melanin unit denotes the symbiotic relationship between one melanocyte transporting melanin via its dendritic processes to approximately 36 keratinocytes [10]. Melanocytes are located on the basement membrane among basal keratinocytes at ratio of 1 melanocyte per 5 basal keratinocytes in hematoxylin and eosin-stained histologic sections. This balance is maintained through regulated induction of melanocyte division. During childhood as the skin surface expands, throughout adulthood to maintain melanocyte numbers, and in response to exposure to sunlight or skin wounding, melanocytes are stimulated to proliferate at a low rate. Melanocyte proliferation entails uncoupling from keratinocytes, loss of their dendrites, cell division, migration along the basement membrane, then recoupling with keratinocytes to form the epidermal melanin unit. Keratinocytes regulate melanocyte growth and expression of melanocyte cell surface receptors via cell adhes...

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“…Because lung metastases in this model did not require angiogenesis, sorafenib and its antiangiogenic properties had no effect. In contrast, Mek inhibition using UO126 decreased tumor cell proliferation thereby significantly reducing lung metastases (8,9,17). Other reports also found sorafenib ineffective at blocking lung adenoma formation compared with the Mek inhibitor CI-1040 (14).…”

Section: Key Findingmentioning

confidence: 96%

Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies?

Madhunapantula¹,

Robertson

2008

Cancer Research

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The RAF family members, A-Raf, B-Raf, and C-Raf (or Raf-1), are intermediate molecules in the mitogen-activated protein (MAP) kinase [Ras/Raf/MAP kinase/extracellular signalregulated kinase (Erk) kinase (MEK)/Erk] pathway, which relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events ultimately promoting cancer development. This pathway is activated by mutation in f7% of all human cancers. B-Raf is one of the proteins frequently mutated to an active form during tumor development. Therefore, B-Raf is an attractive cancer target but lack of clinical efficacy using agents targeting this protein has raised serious doubts about its therapeutic utility. Design of more effective B-Raf inhibitory agents, targeting other members of the signaling cascade for greater clinical efficacy or inhibiting B-Raf in combination with other targets, is being evaluated to resolve these perplexing issues. Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies.

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Sorafenib (BAY 43‐9006, Nexavar®), a Dual‐Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature

Cited by 415 publications

References 28 publications

Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies?

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