Phototoxicity of B-RAF inhibitors: Exclusively due to UVA radiation and rapidly regressive

Gabeff, R.; Dutartre, H.; Khammari, Amir; Boisrobert, Aurélie; Nguyen, Jean–Michel; Quéreux, G.; Brocard, Anabelle; Saint‐Jean, M.; Peuvrel, L.; Dréno, Brigitte

doi:10.1684/ejd.2015.2628

Cited by 19 publications

(16 citation statements)

References 15 publications

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“…Our data support a hypothesis by Gabeff et al that dabrafenib is a phototoxic agent per se but has a different triggering cut‐off for a reaction to UVA radiation compared with vemurafenib. Another explanation for the difference between the high phototoxicity detected in vitro and low frequence of phototoxic adverse events experienced in vivo is the slight delay of dabrafenib studies compared with those of vemurafenib, during which patients had already received the advice for sun‐protection . Furthermore, the cumulative UV absorbance did not correlate well with the phototoxicity observed in the 3T3 assay for all substances.…”

Section: Discussionsupporting

confidence: 92%

“…UVA light plays a more significant role in causing phototoxicity than other UV ranges. 22,23 This is consistent with the results of the ROS assay that was performed in this study with UVA and UVB light. Only 3 out of with UVB light compared with 9 agents which generated ROS after UVA light absorption.…”

Section: Discussionsupporting

confidence: 90%

“…The generation of reactive oxygen species following UV light irradiation can lead to oxidative damage to the cell. UVA light plays a more significant role in causing phototoxicity than other UV ranges . This is consistent with the results of the ROS assay that was performed in this study with UVA and UVB light.…”

Section: Discussionsupporting

confidence: 46%

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Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Heppt

Clanner‐Engelshofen

Marsela

et al. 2019

Photoderm Photoimm Photomed

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Background Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi‐induced phototoxicity can be alleviated by antioxidants. Methods The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. Results The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. Conclusion Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

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Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Heppt

Clanner‐Engelshofen

Marsela

et al. 2019

Photoderm Photoimm Photomed

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“…Several protein kinases inhibitors were reported to have off-target effects. In example, BRAF inhibitor, vemurafenib, used for treating metastatic melanoma[26] with good clinical outcome in some cases[27], was manifested to induce unusual photosensitivity in patients[28]. A recent study by Klaeger et al .…”

Section: Discussionmentioning

confidence: 99%

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

Acedo

Fernandes

Zawacka-Pankau

2018

Preprint

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1The p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in 2 tumors in response to genotoxic stress or small-molecule treatments.3 Pancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds 4 poorly to the existing therapies and has very low overall survival rates. 5Here, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and 6 benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis 7 in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit 8 thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells' 9 vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. 1 0Our findings, may contribute to faster repurposing of PpIX and BPD to treat 1 1 pancreatic tumors. 1 2 Lay Abstract 1 3Despite the efforts, pancreatic cancer remains among the most aggressive tumors.

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“…Dummer et al and our team have previously shown that this photosensitivity was exclusively induced by UVA and defined by a minimum erythema dose (MED) of UVA of <20 joules, present in about 84% of patients and disappearing rapidly upon treatment discontinuation. [1][2][3] Vemurafenib is currently used in combination with cobimetinib, an anti-MEK agent, in advanced or metastatic melanoma.…”

Section: Decreased Photosensitivity To Uva On Vemurafenib Combined Wimentioning

confidence: 99%

Decreased photosensitivity to UVA on vemurafenib combined with cobimetinib

Frénard

Dutartre

Boisrobert

et al. 2018

Acad Dermatol Venereol

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Phototoxicity of B-RAF inhibitors: Exclusively due to UVA radiation and rapidly regressive

Cited by 19 publications

References 15 publications

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

Decreased photosensitivity to UVA on vemurafenib combined with cobimetinib

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