BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies.

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Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review

Journal of Cutaneous Medicine and Surgery ◽

10.1177/12034754211004560 ◽

2021 ◽

pp. 120347542110045

Author(s):

Sara Mirali ◽

Abrahim Abduelmula ◽

Asfandyar Mufti ◽

Muskaan Sachdeva ◽

Jensen Yeung

Keyword(s):

Systematic Review ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Complete Resolution ◽

Kinase Inhibitors ◽

Healthcare Providers ◽

Latency Period ◽

Braf Inhibitors ◽

Palmoplantar Keratoderma ◽

Drug Induced

Background Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK. Methods EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword “palmoplantar keratoderma.” 40 studies met the inclusion criteria. Results A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( n = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, n = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, n = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, n = 8/247), or chemotherapy (2.4%, n = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( n = 12/24) achieving complete resolution and 50% ( n = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( n = 10) and topical corticosteroids ( n = 4). Conclusions PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.

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TRAF1 Is a Critical Regulator of JNK Signaling by the TRAF-Binding Domain of the Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1 but Not CD40

Journal of Virology ◽

10.1128/jvi.77.2.1316-1328.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 1316-1328 ◽

Cited By ~ 42

Author(s):

Aristides G. Eliopoulos ◽

Elyse R. Waites ◽

Sarah M. S. Blake ◽

Clare Davies ◽

Paul Murray ◽

...

Keyword(s):

Membrane Protein ◽

Epstein Barr Virus ◽

Latent Infection ◽

Binding Domain ◽

Cell Phenotype ◽

Tnf Receptor ◽

Jnk Signaling ◽

Barr Virus ◽

Epstein Barr ◽

Jnk Activation

ABSTRACT The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-κB, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type- dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.

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BRAF (v-raf murine sarcoma viral oncogene homolog B1

Atlas of Genetics and Cytogenetics in Oncology and Haematology ◽

10.4267/2042/38125 ◽

2011 ◽

Cited By ~ 2

Author(s):

E Domingo ◽

S Jr Schwartz

Keyword(s):

Viral Oncogene ◽

Murine Sarcoma ◽

Viral Oncogene Homolog

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Concordance and Discordance Rates of V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) V600E Status in Metastatic against Primary Lesion of Melanoma: A Meta-analysis

JMA Journal ◽

10.31662/jmaj.2020-0016 ◽

2020 ◽

Vol 3 (3) ◽

pp. 274-279

Keyword(s):

Meta Analysis ◽

Primary Lesion ◽

Braf V600e ◽

Viral Oncogene ◽

Murine Sarcoma ◽

Viral Oncogene Homolog

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Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834017708160 ◽

2017 ◽

Vol 9 (7) ◽

pp. 481-492 ◽

Cited By ~ 22

Author(s):

Amélie Boespflug ◽

Julie Caramel ◽

Stephane Dalle ◽

Luc Thomas

Keyword(s):

Metastatic Melanoma ◽

Cytotoxic Chemotherapy ◽

Disease Course ◽

Line Treatment ◽

First Line ◽

Viral Oncogene ◽

Melanoma Patients ◽

Murine Sarcoma ◽

Review Current ◽

Viral Oncogene Homolog

The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15–25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS-mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS-mutant melanoma.

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Activation of JNK signaling promotes all-trans-retinal–induced photoreceptor apoptosis in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013189 ◽

2020 ◽

Vol 295 (20) ◽

pp. 6958-6971

Author(s):

Chunyan Liao ◽

Binxiang Cai ◽

Yufeng Feng ◽

Jingmeng Chen ◽

Yiping Wu ◽

...

Keyword(s):

Dna Damage ◽

Intraperitoneal Administration ◽

Photoreceptor Cells ◽

Age Related Macular Degeneration ◽

Jnk Signaling ◽

Age Related ◽

Dry Amd ◽

Induced Apoptosis ◽

Jnk Activation ◽

Species Production

Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4−/−Rdh8−/− mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4−/−Rdh8−/− mice. Of note, intraperitoneal administration of JNK–IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4−/−Rdh8−/− mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.

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Reovirus Infection Activates JNK and the JNK-Dependent Transcription Factor c-Jun

Journal of Virology ◽

10.1128/jvi.75.23.11275-11283.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11275-11283 ◽

Cited By ~ 43

Author(s):

Penny Clarke ◽

Suzanne M. Meintzer ◽

Christian Widmann ◽

Gary L. Johnson ◽

Kenneth L. Tyler

Keyword(s):

Transcription Factor ◽

Host Cell ◽

Receptor Binding ◽

Cell Interaction ◽

Host Cell Membrane ◽

Erk Activation ◽

Reovirus Infection ◽

Induced Apoptosis ◽

Factor C ◽

Jnk Activation

ABSTRACT Viral infection often perturbs host cell signaling pathways including those involving mitogen-activated protein kinases (MAPKs). We now show that reovirus infection results in the selective activation of c-Jun N-terminal kinase (JNK). Reovirus-induced JNK activation is associated with an increase in the phosphorylation of the JNK-dependent transcription factor c-Jun. Reovirus serotype 3 prototype strains Abney (T3A) and Dearing (T3D) induce significantly more JNK activation and c-Jun phosphorylation than does the serotype 1 prototypic strain Lang (T1L). T3D and T3A also induce more apoptosis in infected cells than T1L, and there was a significant correlation between the ability of these viruses to phosphorylate c-Jun and induce apoptosis. However, reovirus-induced apoptosis, but not reovirus-induced c-Jun phosphorylation, is inhibited by blocking TRAIL/receptor binding, suggesting that apoptosis and c-Jun phosphorylation involve parallel rather than identical pathways. Strain-specific differences in JNK activation are determined by the reovirus S1 and M2 gene segments, which encode viral outer capsid proteins (ς1 and μ1c) involved in receptor binding and host cell membrane penetration. These same gene segments also determine differences in the capacity of reovirus strains to induce apoptosis, and again a significant correlation between the capacity of T1L × T3D reassortant reoviruses to both activate JNK and phosphorylate c-Jun and to induce apoptosis was shown. The extracellular signal-related kinase (ERK) is also activated in a strain-specific manner following reovirus infection. Unlike JNK activation, ERK activation could not be mapped to specific reovirus gene segments, suggesting that ERK activation and JNK activation are triggered by different events during virus-host cell interaction.

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