Role of Raf Kinase in Cancer: Therapeutic Potential of Targeting the Raf/MEK/ERK Signal Transduction Pathway

Gollob, Jared; Wilhelm, Scott M.; Carter, Chris; Kelley, Susan L.

doi:10.1053/j.seminoncol.2006.04.002

Cited by 314 publications

(230 citation statements)

References 132 publications

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“…[36][37][38][39] We show that the PI3K/Akt and/or Raf/MEK/MAPK pathways are vital for survival and maintenance of CSCs, because inhibition of these key pathways is sufficient to trigger antiproliferative or cell death effects. Interestingly, these survival pathways mediate their effects by controlling BAD phosphorylation in CSCs.…”

Section: Discussionmentioning

confidence: 87%

“…Substantial number of cancers exhibits increased PI3K/Akt, mitogen-activated protein kinase (MAPK) and Raf signaling. [36][37][38] Although these pathways were shown to modulate survival and self-renewal of CSCs, the precise downstream molecules controlling these properties have not been thoroughly investigated. 39 To test whether Akt-induced survival effects might be mediated through BAD, we inhibited Akt in CSCs and tumorospheres of prostate with LY294002, a PI3K inhibitor, and assessed apoptosis and BAD phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

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Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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“…[65][66][67][68] A recent study demonstrated the utility of cancer genomic profiling by linking such mutations in TSC2 to improved survival for UC patients under everolimus treatment. 69 Amplification of RAF1, which has been linked to high-grade tumor, advanced-stage tumor and poor survival in UC, [70][71][72] was also observed in the series, and can be targeted by kinase inhibitors such as Sorafenib, a multikinase inhibitor whose targets include the Raf1 protein (CRAF). Sorafenib has been approved for use in renal cell carcinoma and hepatocellular carcinoma and is under investigation in clinical trials in multiple solid tumor types.…”

Section: Discussionmentioning

confidence: 99%

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

Wang²,

et al. 2014

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Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 lm of formalin-fixed, paraffinembedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 Â and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0-10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0-7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.

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“…The first oral multi-kinase inhibitor that targets Raf kinases have already been approved for the treatment of renal cell cancer, whereas these factors display a broad spectrum antitumor activity in colon, breast and non-small-cell lung cancer in xenograft models and also hepatocellular carcinoma and sarcoma [38,39]. In this context, the presence of B-raf mutations has been suggested as a possible surrogate marker of sensitivity to those drugs which target the ERK pathway at the level of Raf kinase [38,39]. …”

Section: Discussionmentioning

confidence: 99%

ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics

et al. 2012

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BackgroundColorectal (CRC) carcinogenesis through various morphological stages has been linked to several genetic and epigenetic changes. The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates.MethodsIn this study, we investigated the presence of B-raf and K-ras mutations in 94 consecutive cases of primary colon adenocarcinoma in correlation with the immunohistochemical expression of total and activated ERK and the expression of mismatch repair proteins (MMR) hMLH1 and hMSH2 as well as their correlations with standard clinicopathological parameters.ResultsThe immunostaining pattern for total and activated ERK was nuclear and cytoplasmic. hMLH1 and hMSH2 proteins were preserved in 45/63 (71.43%) cases and 35/53 (66.04%) cases respectively. Total ERK nuclear expression, was positively correlated with tumor stage (p = 0.049), whereas nuclear pERK expression was positively correlated with histological grade (p = 0.0113) and tumor stage (p = 0.0952), although the latter relationship was of marginal significance. DNA sequencing showed that 12 samples (12.7%) had a mutation in B-RAF Exon 15 and none in Exon 11, whereas 22 (23.4%) had a K-ras mutation. Disruption of the MAP kinase pathway-either through K-ras or B-raf mutation-was detected in 37% of all the examined cases, although the overexpression of total and activated ERK1/2 was not correlated with the mutational status of K-ras or B-raf genes. Finally, the preservation of hMLH1 or hMSH2 immunoexpression was not correlated with the presence of B-raf and/or K-ras mutations.ConclusionsIn this study, we present evidence that ERK activation occurs in a K-ras or B-raf -independent manner in the majority of primary colon cancer cases. Moreover, B-raf mutations are not associated with mismatch-repair deficiency through loss of hMLH1 or hMSH2 expression. Activated ERK could possibly be implicated in tumor invasiveness as well as in the acquisition of a more aggressive phenotype.

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Role of Raf Kinase in Cancer: Therapeutic Potential of Targeting the Raf/MEK/ERK Signal Transduction Pathway

Cited by 314 publications

References 132 publications

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics

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