Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery

Thompson, Neil T.; Lyons, John F.

doi:10.1016/j.coph.2005.04.007

Cited by 202 publications

(147 citation statements)

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“…ERK activation was also known to result in GSK3β inactivation and an accumulation of β-catenin in the nucleus 29 , where β-catenin stimulates c-Myc and cyclin D1 transcription that, in turn, facilitate cell proliferation 29,35,36 . Thus, targeting RAS-ERK has been considered a promising approach for inhibition of tumour proliferation and to increase the sensitivity of cancer cells to chemotherapy 4,5 . Several pharmacological reagents have been developed to specifically targeting RAF-MEK-ERK signalling, some of which have been approved for clinical use 4,5 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, targeting RAS-ERK has been considered a promising approach for inhibition of tumour proliferation and to increase the sensitivity of cancer cells to chemotherapy 4,5 . Several pharmacological reagents have been developed to specifically targeting RAF-MEK-ERK signalling, some of which have been approved for clinical use 4,5 . We propose that cancer cells acquire resistance to apoptosis and enhance cell proliferation through orchestrated inhibitions of FOXO3a and GSK3β with activated ERK, …”

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confidence: 99%

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ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

et al. 2008

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The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that ERK downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the nonphosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.The constitutive activation of certain signal transduction cascades leads to the development of tumours and the resistance of tumours to clinical therapy 1,2 . The RAS-ERK pathway triggers one of these cascades and governs many important functions, such as cell fate, differentiation, proliferation and survival in invertebrate and mammalian cells 3,4 . Human tumours frequently overexpress RAS or harbour activated RAS with a point mutation, which contributes substantially to tumour cell growth, invasion and angiogenesis 1, 2 , 5 -8. Cell plasma membrane receptor tyrosine kinases activate RAS GTPases, and GTP-bound RAS activates A-RAF, B-RAF and RAF-1 (ref. 10,17,18,21 , but the E3 ubiquitin ligase responsible for FOXO3a degradation has yet to be identified. MDM2, an E3 ubiquitin ligase plays an important role in the development of multiple human cancers through degrading tumour suppressor proteins, such as p53, RB and E-cadherin [22][23][24][25] . In addition, MDM2 has been shown to be regulated by the RAS-ERK signalling pathway 26 and blocking ERK activity with an MEK1 inhibitor, U0126, reduces MDM2 expression in breast cancer cells 27 .Here, we identify a novel pathway involving the downregulation of FOXO3a expression by RAS-ERK and MDM2, which leads to promotion of cell growth and tumorigenesis. We show that ERK interacts with and phosphorylates FOXO3a at Ser 294, Ser 344 and Ser 425; phosphorylation of FOXO3a at these residues increases FOXO3a-MDM2 interaction and enhances FOXO3a degradation via an MDM2-dependent ubiquitin-proteasome pathway. The non-phosphorylated FOXO3a-mimic mutant, compared to the phosphorylated FOXO3a-mimic mutant, exhibits more resistance to the interaction and degradation by MDM2, resulting in a strong inhibition of cell proliferation in vitro and tumorigenesis in vivo. RESULTS ERK suppresses FOXO3a stability and induces its nuclear exclusionThe RAS-ERK is an essential oncogenic signalling cascade that promotes tumour cell growth and development 8,28 . It was known that other oncogenic kinases, AKT and IKK, (Fig. 1b, c). Similarly, using Erk small interference RNA (siRNA) to knockdown ERK protein expression level in HeLa cells (Fig. 1d), or trea...

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Section: Discussionmentioning

confidence: 99%

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ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

et al. 2008

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“…Each of these nodes has been explored for therapeutic intervention in oncology with both successes and failures (12)(13)(14). Activating mutations in B-Raf are particularly prevalent in melanoma (∼60%), thyroid (∼35%), and colorectal (∼10%) cancers.…”

Section: Activating Mutations In Ras and Raf Occur In Tumorsmentioning

confidence: 99%

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Carnahan

Beltran

Babij

et al. 2010

Molecular Cancer Therapeutics

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Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., V600E B-Raf A375, IC 50 on cells = 2 nmol/L; ED 50 on tumor xenografts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors resulted in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some of these cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimulated tumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interfering RNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or C-Raf mediated the Raf inhibitor-induced mitogen-activated protein kinase pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro and in vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399-410. ©2010 AACR.

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“…Both isoforms inhibited the Ras/MAPK pathway, and hSef-a also inhibited PI-3K signaling (Xiong et al, 2003;Yang et al, 2003;Preger et al, 2004;Torii et al, 2004, Ziv et al, 2006. Proteins in these pathways are known to be subverted by oncogenic mutations in a variety of human cancers (Blume-Jensen and Hunter, 2001; Thompson and Lyons, 2005). Given the inhibitory effect of hSef on RTK signaling, it is conceivable that its loss of function leads to unchecked cell proliferation in malignancy.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas

et al. 2007

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Carcinomas are tumors of epithelial origin accounting for over 80% of all human malignancies. A substantial body of evidence implicates oncogenic signaling by receptor tyrosine kinases (RTKs) in carcinoma development. Here we investigated the expression of Sef, a novel inhibitor of RTK signaling, in normal human epithelial tissues and derived malignancies. Human Sef (hSef) was highly expressed in normal epithelial cells of breast, prostate, thyroid gland and the ovarian surface. By comparison, substantial downregulation of hSef expression was observed in the majority of tumors originating from these epithelia. Among 186 primary carcinomas surveyed by RNA in situ hybridization, hSef expression was undetectable in 116 cases including 72/99 (73%) breast, 11/16 (69%) thyroid, 16/31 (52%) prostate and 17/40 (43%) ovarian carcinomas. Moderate reduction of expression was observed in 17/186, and marked reduction in 40/186 tumors. Only 13/186 cases including 12 low-grade and one intermediate grade tumor retained high hSef expression. The association of hSef downregulation and tumor progression was statistically significant (Po0.001). Functionally, ectopic expression of hSef suppressed proliferation of breast carcinoma cells, whereas inhibition of endogenous hSef expression accelerated fibroblast growth factor and epidermal growth factor-dependent proliferation of cervical carcinoma cells. The inhibitory effect of hSef on cell proliferation combined with consistent downregulation in human carcinoma indicates a tumor suppressor-like role for hSef, and implicates loss of hSef expression as a common mechanism in epithelial neoplasia.

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Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery

Cited by 202 publications

References 19 publications

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas

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