The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer

Hilger, Ralf A.; Scheulen, M. E.; Strumberg, Dirk

doi:10.1159/000068621

Cited by 213 publications

(180 citation statements)

References 57 publications

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“…other orally MAPK inhibitor, could induce a stabilization of the disease without however causing neither a strong reduction nor the disappearance of the tumor (Hilger et al, 2002). Interestingly, in our study, intraperitoneal injection of U0126 decreased tumor engraftment and growth.…”

Section: Discussioncontrasting

confidence: 55%

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

et al. 2008

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The MAPK MEK/ERK pathway is often upregulated in cancer cells and represents an attractive target for development of anticancer drugs. Only few data concerning the specific functions of ERK1 and 2 are reported in the literature. In this report, we investigated the specific role of ERK1 and 2 in liver tumor growth both in vitro and in vivo. DNA synthesis and cells in S phase analysed by flow cytometry, correlated with strong inhibition of Cdk1 and cyclin E levels, are strongly reduced after exposure to the MEK inhibitor, U0126. We obtained a significant reduction of colony formation in soft agar assays and a reduction in the size of tumor xenografts in nude mice treated with U0126. Then, we could specifically abolished ERK1 or 2 expression by small-interfering RNA (siRNA) and demonstrated that ERK2 knockdown but not ERK1 interferes with the process of replication. Moreover, we found that colony formation and tumor growth in vivo were significantly inhibited by targeting ERK2 using stable chemically modified siRNA. Taken together, our results emphasize the importance of the MEK/ERK pathway in liver cancer cell growth in vitro and in vivo and argue for a crucial role of ERK2 in this regulation.

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Section: Discussioncontrasting

confidence: 55%

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

et al. 2008

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“…6,8,21,28 As somatic mutations leading to the expression of oncogenic N-Ras are known to arise early in melanoma development and be maintained throughout melanoma progression, 11,29 oncogenic NRAS represents an attractive therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Such mutations that change the protooncogene RAS to an active oncogene are found in approximately 30 to 50% of human tumors. [4][5][6][7][8] Ras has also been demonstrated to be important for both the genesis and maintenance of melanoma. For instance, in a doxycycline-inducible H-Ras V12G mouse melanoma model, withdrawal of doxycycline was demonstrated to result in histological regression of primary and implanted tumors accompanied by marked apoptosis of melanoma cells.…”

mentioning

confidence: 99%

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

Eskandarpour¹,

Kiaii²,

Zhu³

et al. 2005

Intl Journal of Cancer

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The majority of human melanomas harbor activating mutations in either the BRAF or NRAS gene. To date, the role of oncogenic NRAS in melanoma remains poorly defined and no current therapies are directed at specifically suppressing oncogenic NRAS in human melanoma tumors. The aim of our study, therefore, was to investigate the effects of suppressing oncogenic NRAS in human melanoma cell lines in vitro. Using both small interfering RNAand plasmid based-RNA interference techniques, oncogenic NRAS was specifically suppressed in 2 human melanoma cell lines, 224 and BL, which harbor a codon 61 CAA (glutamine) to CGA (arginine) NRAS mutation. Suppression of oncogenic NRAS in these cell lines resulted in increased apoptosis. Furthermore, in 224 cells we demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and reduced expression of NF-kB and cyclin D1 in the N-Ras signaling pathway. In contrast, RNA interference directed at wild-type (WT) NRAS had no significant effect on apoptosis of 224 cells or 2 human melanoma cell lines (A375 and 397) containing WT NRAS but a codon 600 GTG (valine) to GAG (glutamate) mutation in BRAF. These data suggest that oncogenic NRAS is important for avoidance of apoptosis in melanomas that harbor the codon 61 NRAS mutation and emphasizes oncogenic NRAS as a therapeutic target in patients with tumors that harbor this mutation. ' 2005 Wiley-Liss, Inc.Key words: RNAi; melanoma; Ras; signal transduction; apoptosis Activation of Ras is a common molecular event in the etiology of human cancer. 1 The Ras proteins H-, K-and N-Ras are central regulators of cellular signal transduction processes leading to cell growth and differentiation. In the resting cell, Ras proteins are in the guanosine diphosphate (GDP)-bound inactive state. However, in response to receptor protein tyrosine kinases or other growth factor-dependent stimuli, these Ras proteins become activated by binding guanosine triphosphate (GTP). 2,3 Oncogenic mutations in codons 12, 13 and 61 of RAS genes prevent GTP hydrolysis, resulting in constitutively active Ras proteins. Such mutations that change the protooncogene RAS to an active oncogene are found in approximately 30 to 50% of human tumors. [4][5][6][7][8] Ras has also been demonstrated to be important for both the genesis and maintenance of melanoma. For instance, in a doxycycline-inducible H-Ras V12G mouse melanoma model, withdrawal of doxycycline was demonstrated to result in histological regression of primary and implanted tumors accompanied by marked apoptosis of melanoma cells. 9 Studies on melanoma tumors have confirmed that oncogenic activation of NRAS constitutes the predominant RAS alteration in cutaneous melanoma, with NRAS codon 61 mutations being the most common alterations and codon 12 and 13 mutations being less frequent. 6,7,10,11 In sporadic melanoma cases, the frequency of NRAS alterations reported varies in different studies. [12][13][14] In a study performed by our group, 28% of primary melanomas and 37% of metastatic tumo...

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“…Cell proliferation, differentiation, and development are all initiated within the RAS/RAF/MEK/ERK pathway, thus it often sustains multiple mutations in various cancer types [91]. MEK1/2 inhibitors used with EGFR or VEGFR TKIs have demonstrated growth inhibition, antiangiogenesis, and curbed metastasis.…”

Section: Simultaneously Targeting Major Oncogenic Pathways By Multiplmentioning

confidence: 99%

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Kemp

Shim

Heo

et al. 2016

Advanced Drug Delivery Reviews

406

242

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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

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The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer

Cited by 213 publications

References 57 publications

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

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