Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma

Hong, Xiao; Piao, Sheng Fu; Dey, Souvik; McAfee, Quentin; Karakousis, Giorgos C.; Villanueva, Jessie; Hart, Lori S.; Levi, Samuel M.; Hu, Janice; Zhang, Gao; Lazova, Rossitza; Klump, Vincent; Pawelek, John M.; Xu, Xiaowei; Xu, Wei; Schuchter, Lynn M.; Davies, Michael A.; Herlyn, Meenhard; Winkler, Jeffrey D.; Koumenis, Constantinos; Amaravadi, Ravi K.

doi:10.1172/jci70454

Cited by 366 publications

(418 citation statements)

References 53 publications

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“…Expression of oncogenic BRAF in SK-Mel-110 cells, as evidenced by ERK1/2 hyperphosphorylation (Figure 2c), resulted in a clear upregulation of mRNA coding for ERp57, ATF4, ERdj5 and Xbp-I (Figure 2b), increased levels of both calnexin and ERp57 proteins and eIF2α phosphorylation (Figure 2d), as well as enhanced Xbp-I splicing (Figure 2e), confirming that BRAF mutation is solely responsible for ER compartment deregulation, and compatible with a chronic ER stress status. These data thus support recent observations of increased ER stress as a consequence of BRAF therapy-induced resistance by Ma and co-workers, 34 and provide additional insight into the mechanisms mediating increased basal ER stress in BRAFmutated melanoma cells.…”

Section: Resultssupporting

confidence: 90%

“…To our knowledge chemical chaperones are, at present, the only available molecules able to effectively reduce ER stress both in vitro and in vivo 44 and because in the present study, prolonged 4-PBA treatment of BRAF-mutated melanoma cells resulted in the reduced expression of both markers of ER stress and basal autophagy as well as increased sensitivity to pro-apoptotic drugs, the clinical use of chemical chaperones may thus harness ER stress and autophagy modulation for the therapeutic benefit of patients bearing BRAF V600E tumours. Recent studies by Ma et al 34 identified ER stress and autophagy induction as a mechanism mediating resistance to BRAF inhibitor therapy in patients bearing BRAF V600E mutant melanomas suggesting a direct link between these two pathways. Our data thus complement the studies of Ma et al 34 and provide additional novel molecular insight into how oncogenic BRAF leads to a chronic ER stress state and the promotion of basal autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies by Ma et al 34 identified ER stress and autophagy induction as a mechanism mediating resistance to BRAF inhibitor therapy in patients bearing BRAF V600E mutant melanomas suggesting a direct link between these two pathways. Our data thus complement the studies of Ma et al 34 and provide additional novel molecular insight into how oncogenic BRAF leads to a chronic ER stress state and the promotion of basal autophagy. Moreover, given observations of ER chemical chaperone-mediated resensitization of BRAF V600E melanoma cells to a panel of pro-apoptotic drugs, able to activate different apoptotic pathways, the use of drugs able to harness ER stress or, alternatively, to target the molecular pathways linking BRAF V600E -induced ER stress and basal autophagy (such as the IRE1/TRAF2/ASK1/JNK and the TRB3 axes) for the clinical benefit of such tumours is warranted.…”

Section: Discussionmentioning

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: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…This is in concordance with our finding that the two MGP melanoma cell lines, WM983-B and SK-MEL-5, that had received DMSO only, showed an LC3-positive phagosome signal in less than 1% of the cells and that the level of p62/ SQSTM1 expression in the DMSO-treated WM983-B cells was low. On the other hand, recent and increasing evidence, obtained primarily in the context of melanoma-BRAF inhibitor resistance studies, suggests that autophagy is a pertinent survival mechanism for advanced melanoma (32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Turriani

Lázaro

Ryazanov

et al. 2017

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

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Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell's survival. melanoma | Parkinson's disease | α-synuclein | oligomer modulator treatment | autophagy

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“…In turn, pharmacological inhibition of autophagy potentiates OncTK/RTK targeted therapy. 2,28,[38][39][40][41] In particular, autophagy has been placed downstream of two RTKs with a known role in cancer, the Epidermal Growth Factor Receptor (EGFR) 17,19,[42][43][44][45][46][47][48][49][50] and the Hepatocyte Growth Factor Receptor (HGFR), c-MET. 51 EGFR has been suggested to regulate autophagy either directly 17,19 or indirectly through its downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

et al. 2017

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The intracellular autophagic degradative pathway can play tumour suppressive or tumour promoting roles depending on the stage of tumour development. Upon starvation or targeting of oncogenic receptor tyrosine kinases (RTKs), autophagy is activated due to inhibition of PI3K/AKT/mTORC1 signalling pathway and promotes survival, suggesting that autophagy is a relevant therapeutic target in these settings.

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Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma

Cited by 366 publications

References 53 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

Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

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