Mutant B-RAF mediates resistance to anoikis via Bad and Bim

Boisvert-Adamo, Karen; Aplin, Andrew E.

doi:10.1038/sj.onc.1211003

Cited by 90 publications

(85 citation statements)

References 37 publications

(55 reference statements)

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“…ERK1/2 signaling modulates apoptotic events through regulation of Bcl-2 family proteins in melanoma cells. 49 We have shown that apoptosis resistance is due to the silencing of two BH3-only proteins, Bim-EL and Bmf, via a mechanism which is largely independent of ERK1/2 reactivation. Our results from bisulfite sequencing analysis of the Bim-EL and Bmf promoters and 5-azacytidine treatment argue against promoter methylation being sufficient to explain the silencing of Bim-EL and Bmf and, hence, resistance to PLX4720.…”

Section: Discussionmentioning

confidence: 91%

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

Shao

Aplin

2012

Cell Death Differ

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B-RAF is mutated to a constitutively active form in 8% of human cancers including 50% of melanomas. In clinical trials, the RAF inhibitor, PLX4032 (vemurafenib), caused partial or complete responses in 48-81% of mutant B-RAF harboring melanoma patients. However, the average duration of response was 6-7 months before tumor regrowth, indicating the acquisition of resistance to PLX4032. To understand the mechanisms of resistance, we developed mutant B-RAF melanoma cells that displayed resistance to RAF inhibition through continuous culture with PLX4720 (the tool compound for PLX4032). Resistance was associated with a partial reactivation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, recovery of G1/S cellcycle events, and suppression of the pro-apoptotic B-cell leukemia/lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins, Bcl-2-interacting mediator of cell death-extra large (Bim-EL) and Bcl-2 modifying factor (Bmf). Preventing ERK1/2 reactivation with MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) inhibitors blocked G1-S cell-cycle progression but failed to induce apoptosis or upregulate Bim-EL and Bmf. Treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid, led to de-repression of Bim-EL and enhanced cell death in the presence of PLX4720 or AZD6244 in resistant cells. These data indicate that acquired resistance to PLX4032/4720 likely involves ERK1/2 pathway reactivation as well as ERK1/2-independent silencing of BH3-only proteins. Furthermore, combined treatment of HDAC inhibitors and MEK inhibitors may contribute to overcoming PLX4032 resistance. Oncogene addiction refers to the dependence of tumor cells on the continued expression of an oncogene for the maintenance of malignant properties.1 It has gained increasing recognition in recent years and provides the rationale for targeted therapeutic strategies. Notable advances are the responses of chronic myelogenous leukemia patients with BCR-ABL (breakpoint cluster region-v-abl abelson murine leukemia viral oncogene homolog 1) translocations to imatinib, breast cancer patients with amplified human epidermal receptor 2 (HER2) to trastuzumab, and mutant epidermal growth factor receptor (EGFR)-harboring nonsmall cell lung carcinomas patients to erlotinib and gefitinib treatments.2-4 A more recent example is the strategy to target mutations in the serine/threonine kinase B-RAF that occur in B50% of melanomas, 30% of thyroid carcinomas, and 14% of colorectal tumors.5 A valine to glutamic acid substitution at codon 600 (V600E) accounts for over 90% of the mutations in B-RAF and activates B-RAF kinase activity toward the MEKextracellular signal-regulated kinase 1/2 (ERK1/2) cascade. B-RAFV600E and MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) activity are required for melanoma cell proliferation, invasion, and resistance to apoptosis in vitro, 6-11 and tumor xenograft growth in immunocompromised mice. 8,12 Furthermore, conditional melanocyte-specific expr...

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Section: Discussionmentioning

confidence: 91%

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

Shao

Aplin

2012

Cell Death Differ

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“…Indeed, studies have suggested that ERK1/2 signalling protects melanoma cells from anoikis by inhibiting both BAD and BIM. 62,63 Inhibition of ERK1/2 signalling increased the abundance of both BIM and BAD and their combined knockdown strongly inhibited death arising from BRAF knockdown. 63 In a separate study, melanoma cell lines with high levels of ERK1/2 signalling underwent apoptosis when treated with U0126 and the increase in BIM and PUMA and the loss of MCL-1 appeared to play the critical role in cell death.…”

Section: Badmentioning

confidence: 99%

“…62,63 Inhibition of ERK1/2 signalling increased the abundance of both BIM and BAD and their combined knockdown strongly inhibited death arising from BRAF knockdown. 63 In a separate study, melanoma cell lines with high levels of ERK1/2 signalling underwent apoptosis when treated with U0126 and the increase in BIM and PUMA and the loss of MCL-1 appeared to play the critical role in cell death. 64 ERK1/2 signalling can also provide protection against chemotherapeutic cytotoxic drugs.…”

Section: Badmentioning

confidence: 99%

Tumour cell survival signalling by the ERK1/2 pathway

2008

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Several advances in recent years have focused increasing attention on the role of the RAF-MEK-ERK1/2 pathway in promoting cell survival. The demonstration that BRAF is a human oncogene mutated at high frequency in melanoma, thyroid and colon cancer has provided a pathophysiological context, whilst the description of potent and highly selective inhibitors of BRAF or MEK has allowed a more informed and rational intervention in both normal and tumour cells. In addition, separate studies have uncovered new mechanisms by which the ERK1/2 pathway can control the activity or abundance of members of the BCL-2 protein family to promote cell survival. It is now apparent that various oncogenes co-opt ERK1/2 signalling to de-regulate these BCL-2 proteins and this contributes to, and even underpins, survival signalling in some tumours. New oncogene-targeted therapies allow direct or indirect inhibition of ERK1/2 signalling and can cause quite striking tumour cell death. In other cases, inhibition of the ERK1/2 pathway may be more effective in combination with other conventional and novel therapeutics. Here, we review recent advances in our understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies.

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“…For instance, Raf-MEK-Erk signalling has been shown to increase the expression of several pro-survival Bcl-2 proteins by down-regulating pro-apototic Bcl-2/Bcl-XL-associated death promoter (Bad) and by promoting de novo gene expression of Bcl-2, Bcl-XL, and Mcl-1 (Boucher et al 2000, Boisvert-Adamo & Aplin 2008, Balmanno & Cook 2009). Consistently, inhibition of Raf-MEK-Erk signalling induced apoptosis in numerous tumour models (Balmanno & Cook 2009).…”

Section: Nvp-aew541+trailmentioning

confidence: 99%

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

Zitzmann

Toni²,

Rüden³

et al. 2011

Endocrine Related Cancer

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The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro-and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP S , caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP S or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

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Mutant B-RAF mediates resistance to anoikis via Bad and Bim

Cited by 90 publications

References 37 publications

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

Tumour cell survival signalling by the ERK1/2 pathway

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

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