Do the Side Effects of BRAF Inhibitors Mimic RASopathies?

Sfecci, Alicia; Dupuy, Alain; Dinulescu, M.; Droitcourt, Catherine; Adamski, H.; Hadj‐Rabia, Smail; Odent, Sylvie; Galibert, Marie‐Dominique; Boussemart, Lise

doi:10.1016/j.jid.2016.12.012

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…Consistent with this mechanism, there is evidence for paradoxical hyperactivation of the MAPK pathway in cells with wild-type BRAF but mutated RAS through allosteric and catalytic mechanisms that relieve the auto-inhibition of wild-type RAF kinase ( Hatzivassiliou et al, 2010 ; Heidorn et al, 2010 ; Poulikakos et al, 2010 ). Indeed, many of these BRAFi features overlap with the cutaneous manifestations of RASopathies – genetic diseases such as cardiofaciocutaneous and Costello syndromes characterized by activating germ line mutations in RAS ( Rinderknecht et al, 2013 ; Sfecci et al, 2017 ). Also consistent with this, 18–60% of BRAFi-cSCC have somatic mutations in HRAS or KRAS, which is significantly higher than in sporadic cSCC ( Oberholzer et al, 2012 ; Su et al, 2012 ; South et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

et al. 2018

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Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC.Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays.Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden.Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.

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Section: Introductionmentioning

confidence: 99%

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

et al. 2018

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“…This could be explained either by a synergistic effect of the combination therapy or by an inhibition of the paradoxical activation of MAPK pathway observed under BRAF inhibitors alone (Holderfield, Nagel, & Stuart, ). In fact a paradoxical activation of MAPK pathway has been described with single inhibition of BRAF in the BRAF ‐wild‐type nonmelanoma cells, explaining most of side effects of the monotherapy such as cutaneous squamous‐cell carcinomas under BRAF inhibitors (Lacouture, O'Reilly, Rosen, & Solit, ; Su et al, ) or skin effects of single inhibition mimicking RASopathies (Sfecci et al, ). However, this paradoxical activation could prevent the dilutional hyponatremia observed under BRAF inhibitors alone.…”

Section: Pathophysiological Aspectsmentioning

confidence: 99%

“…RASopathies (Sfecci et al, 2017). However, this paradoxical activation could prevent the dilutional hyponatremia observed under BRAF inhibitors alone.…”

Section: Pathophys Iolog Ic Al a S Pec Tsmentioning

confidence: 99%

Hyponatremia and MAP‐kinase inhibitors in malignant melanoma: Frequency, pathophysiological aspects and clinical consequences

Assan

Vilaine

Wagner

et al. 2018

Pigment Cell Melanoma Res

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The incidence of malignant melanoma has increased over the past two decades. A combined BRAF/MEK inhibitor regimen has been shown to lead to prolonged survival and progression‐free survival in patients with metastatic BRAF V600‐mutant melanoma. Different nephrotoxic effects have been described, among them hyponatremia. The goal of the present narrative review was to understand the pathophysiological mechanisms driving hyponatremia when using selective BRAF inhibitors and/or MEK inhibitors in order to propose potential strategies to prevent or to treat this side effect. Several mechanisms of kidney injury have been suggested including changes in glomerular and tubular function. However, the precise mechanisms of hyponatremia remain unknown. Our hypothesis is that BRAF/MEK inhibitors lead to hyponatremia and water retention (so‐called dilution hyponatremia) by activating aquaporin 2 (AQP2) trafficking from its intracellular compartment to the luminal cell membrane, and by activating ENaC channel. Therefore, we recommend treating the hyponatremia related to BRAF/MEK inhibitors with restriction of fluid intake.

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“…Cutaneous adverse event profiles of BRAF and MEK inhibitors are very distinct, and unlike many other combinations some specific cutaneous adverse events occur less frequently when BRAF and MEK inhibitors are used concomitantly. A paradoxical activation of the MAPK pathway induced by BRAF inhibitors in BRAF wild‐type cells is thought to be counteracted by MEK inhibitors that block a kinase downstream of RAF and vice versa.…”

mentioning

confidence: 99%

Evaluation of cutaneous adverse events of encorafenib and binimetinb: COMMENT on article by Graf et al.

Livingstone

2019

Acad Dermatol Venereol

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Since the approval of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib, three different combination regimens for BRAF-mutated advanced melanoma are now available in Europe and we are somewhat spoilt for choice. None of the three combination treatments (encorafenib plus binimetinib, dabrafenib plus trametinb and vemurafenib plus cobimetinib) have ever been tested head-to-head within a clinical trial. 1-3 Cross-trial comparisons have to be made with caution as clinical trial set-up, demographics as well as time of trial recruitment and available treatment options differ. Yet, when advising patients on treatment, one must know differences in response rate, duration of response but also adverse events. BRAF as well as MEK inhibitors are notorious for cutaneous adverse events. Both inhibitors block a kinase within the MAPK pathway, but while BRAF inhibitors primarily bind to mutated BRAF, MEK inhibitors bind to wild-type MEK. Cutaneous adverse event profiles of BRAF and MEK inhibitors are very distinct, and unlike many other combinations some specific cutaneous adverse events occur less frequently when BRAF and MEK inhibitors are used concomitantly. A paradoxical activation of the MAPK pathway induced by BRAF inhibitors in BRAF wild-type cells 4 is thought to be counteracted by MEK inhibitors that block a kinase downstream of RAF and vice versa.While cutaneous adverse events are well described for first-generation BRAF and MEK inhibitors, Graf et al. 5 aimed to describe the cutaneous toxicity profiles of encorafenib, binimetinib and their combination. To this end, they retrospectively reviewed charts of patients treated with BRAF and/or MEK inhibitors in clinical trials at the University Hospital Zurich. Results for encorafenb, binimetinib and their combination were then compared to dabrafenib, vemurafenib, cobimetinib and trametinib. A total of 111 patients receiving 123 treatments were identified. Unfortunately, some groups (e.g. vemurafenib monotherapy) were very small with <10 patients making comparisons difficult. According to their data, cutaneous adverse events were lower in patients treated with encorafenib plus binimetinib (32.7%) than any other mono-or combination therapy (45.4-100%). Encorafenib induced less keratinocytic disorders than vemurafenib; encorafenib's most frequent cutaneous adverse events were palmoplantar erythrodysesthesia (58.3%) and palmoplantar hyperkeratosis (54.2%) followed by alopecia (45.8%). Cutaneous adverse event profiles of binimetinib were similar to trametinib, drug-induced papulopustular eruptions ranked first for both MEK inhibitors (64% and 75%, respectively). When combining encorafenib and binimetinib, all cutaneous adverse events of the single agents decreased to less or around 10%. Graf et al. 5 argue that the lower toxicity rate of encorafenib is a consequence of a lower paradoxical activation of the MAPK pathway 6 and encorafenib's longer dissociation time. 7,8 Even though conclusions from this investigation must be drawn with caution due to the low patien...

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Do the Side Effects of BRAF Inhibitors Mimic RASopathies?

Cited by 8 publications

References 39 publications

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

Hyponatremia and MAP‐kinase inhibitors in malignant melanoma: Frequency, pathophysiological aspects and clinical consequences

Evaluation of cutaneous adverse events of encorafenib and binimetinb: COMMENT on article by Graf et al.

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