BRAF Signaling and Targeted Therapies in Melanoma

Dhomen, Nathalie; Marais, Richard

doi:10.1016/j.hoc.2009.04.001

Cited by 167 publications

(144 citation statements)

References 81 publications

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“…As autophagy is primarily a pro-survival pathway actively counteracting the apoptotic process, high basal autophagy levels may account for, at least in part, the notorious resistance of BRAF-mutated melanoma cells to ER stress-induced apoptosis, 17 as confirmed in Figure 1e also showing that A375 cells are more resistant to thapsigargin-induced apoptosis, compared with CHL-1 cells.…”

Section: Resultsmentioning

confidence: 83%

“…14 Indeed, up to 90% of all melanomas harbour activating NRAS or BRAF mutations, with BRAF V600E representing more than 90% of BRAF mutations, 15,16 the consequence of which is the constitutive activation of RAF-extracellular signal-regulated kinase/ERK signalling promoting melanoma proliferation and resistance to apoptosis. 17 Nevertheless, mutation of NRAS/ BRAF alone is not sufficient to initiate melanomagenesis, because these common mutations are also present in benign nevi, thereby highlighting the requirement of other factors to drive melanocyte transformation and melanoma development. 15,16 Dysregulation of autophagy has accordingly been postulated as a secondary event contributing to melanoma progression and, importantly, also has a key role in chemoresistance.…”

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confidence: 99%

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Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

et al. 2014

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The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF V600E mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF V600E induces a chronic ER stress status directly increasing basal cell autophagy. BRAF V600E -mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF V600E -mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF V600E melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.

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Section: Resultsmentioning

confidence: 83%

mentioning

confidence: 99%

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

et al. 2014

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“…More than half of melanomas harbor activating V600E mutation of BRAF (BRAFV600E) (Long et al ., 2012), a critical driver gene for the proliferation and survival of melanoma cells through the activation of MAPK pathway (Dhomen and Marais, 2009; Fecher et al ., 2008). MEK inhibitors, such as AZD6244 (Selumetinib ® ), have been approved for uveal melanoma by FDA.…”

Section: Introductionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

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“…The three Raf proteins are now known to associate as homodimers or heterodimers (6,14,15). In one current model, B-Raf is viewed as the major pathway activator, whereas C-Raf and A-Raf fine tune the signal to impact intensity and/or duration of ERK1/2 activity (7,16). B-Raf/C-Raf heterodimers have higher activity than B-Raf or C-Raf homodimers and may produce distinct ERK1/2 activation kinetics (15).…”

mentioning

confidence: 99%

Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback

Duan

Cobb

2010

Proc. Natl. Acad. Sci. U.S.A.

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In pancreatic β cells, ERK1 and ERK2 participate in nutrient sensing, and their activities rise and fall as a function of glucose concentration over the physiologic range. Glucose metabolism triggers calcium influx and release of calcium from intracellular stores to activate ERK1/2. Calcium influx also activates the calcium-dependent phosphatase calcineurin, which is required for maximal ERK1/2 activation by glucose. Calcineurin controls insulin gene expression by ERK1/2-dependent and -independent mechanisms. Here, we show that, in β cells, glucose activates the ERK1/2 cascade primarily through B-Raf. Glucose activation of B-Raf, like that of ERK1/2, is calcineurin-sensitive. Calcineurin binds to B-Raf in both unstimulated and stimulated cells. We show that B-Raf is a calcineurin substrate; among calcineurin target residues on B-Raf is T401, a site of negative feedback phosphorylation by ERK1/2. Blocking calcineurin activity in β cells prevents dephosphorylation of B-Raf T401 and decreases B-Raf and ERK1/2 activities. We conclude that the major calcineurin-dependent event in glucose sensing by ERK1/2 is the activation of B-Raf.

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BRAF Signaling and Targeted Therapies in Melanoma

Cited by 167 publications

References 81 publications

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback

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