MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer

Purpose The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. Methods Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. Results Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. Conclusions Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management. (AU)

Eficacia del implante de dexametasona intravítreo en el manejo del «síndrome de Vogt-Koyanagi-Harada-like» secundario a la inhibición de la vía MAP quinasa / Usefulness of intravitreal dexamethasone implant in the management of «Vogt-Koyanagi-Harada-like syndrome» secondary to map kinase pathway inhibition

Mujer de 58 años, con antecedentes personales de melanoma metastásico en tratamiento con trametinib y dabrafenib, que presentaba disminución de agudeza visual bilateral. En la exploración se podía observar uveítis anterior, vitritis, desprendimiento de retina seroso, vasculitis y edema de disco en ambos ojos; se la diagnosticó de síndrome de Vogt-Koyanagi-Harada-like secundario a inhibición de la vía MAP quinasa. Además de la retirada de los fármacos oncológicos, se pautaron corticoides sistémicos y tópicos, pero este tratamiento consiguió solo una mejoría parcial del cuadro cuando se reintrodujo la terapia biológica; se añadió, por tanto, un implante de dexametasona intravítreo bilateral que consiguió una evolución favorable en su sintomatología y en los hallazgos de las pruebas complementarias. La inflamación intraocular es una complicación descrita tras el tratamiento con trametinib y dabrafenib. Un diagnóstico preciso unido al tratamiento corticoideo, tanto sistémico como intravítreo, nos llevó a obtener óptimos resultados

The case is presented of a 58-year-old woman with a personal history of metastatic melanoma under treatment with trametinib and dabrafenib, as well as a decrease in bilateral visual acuity. On examination, it was observed that she had an anterior uveitis, vitritis, serous retinal detachment, vasculitis and disc oedema in both eyes. She was diagnosed with a Vogt-Koyanagi-Harada-like syndrome secondary to MAP kinase pathway inhibition. In addition to the withdrawal of the oncology drugs, systemic and topical corticosteroids were prescribed, but this treatment only achieved a partial improvement of the disease when biological therapy was re-introduced. Therefore, a bilateral intravitreal dexamethasone implant was added, which led to a favourable progression in her symptomatology, as well as in the findings of complementary tests. Intraocular inflammation is a complication described after treatment with trametinib and dabrafenib. An accurate diagnosis, added to corticosteroid treatment, systemic and intravitreal, led us to obtain optimal results

MAP3K kinases and kidney injury / MAP3K quinasas y daño renal

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored

Las proteínas quinasas activadas por mitógenos (MAP quinasas) son quinasas conectadas funcionalmente que regulan procesos celulares clave involucrados en la enfermedad renal como la supervivencia, la muerte, la diferenciación y la proliferación. El típico módulo MAP quinasa está compuesto por una cascada de 3 quinasas: una MAP quinasa quinasa quinasa (MAP3K) que fosforila y activa una MAP quinasa quinasa (MAP2K) que, a su vez, fosforila una MAP quinasa (MAPK). Si bien el papel de las MAPK como ERK, p38 y JNK se ha caracterizado bien en las lesiones renales experimentales, se sabe mucho menos acerca de las quinasas apicales en la cascada, las MAP3K. Hay 24 MAP3K (MAP3K1 a MAP3K21, más RAF1, BRAF y ARAF). En este trabajo revisamos el conocimiento actual sobre la participación de MAP3K en la enfermedad renal no maligna y las herramientas terapéuticas disponibles. Existe evidencia intervencionista experimental in vivo que respalda claramente el papel de MAP3K5 (ASK1) y MAP3K14 (NIK) en la patogenia de la enfermedad renal experimental. De hecho, el inhibidor de ASK1, selonsertib, ha sido estudiado en ensayos clínicos en la enfermedad renal diabética. Además, aunque la MAP3K7 (MEKK7, TAK1) es necesaria para el desarrollo renal, la inhibición de MAP3K7 en el adulto protegió de la lesión renal aguda y crónica experimental; e inhibir MAP3K8 (TPL2/Cot) protegió de la lesión renal aguda. Por el contrario, MAP3K15 (ASK3) puede proteger de la hipertensión y los inhibidores de BRAF, en uso clínico, pueden inducir lesión renal aguda y síndrome nefrótico. Dado su papel como reguladores de los primeros pasos de la señalización intracelular, las MAP3K son posibles dianas terapéuticas en la lesión renal, como se ha demostrado para algunas de ellos. Sin embargo, el papel de la mayoría de las MAP3K en la enfermedad renal no ha sido explorado

Uveítis y desprendimiento seroso de retina secundarios al tratamiento sistémico con dabrafenib y trametinib / Uveitis and serous retinal detachment secondary to systemic dabrafenib and trametinib

Caso clínico: Presentamos el caso de una mujer de 39 años de edad con un melanoma metastásico en tratamiento con dabrafenib y trametinib, que desarrolló una panuveítis severa aguda con uveítis anterior granulomatosa, asociada a vitritis y múltiples desprendimientos serosos de retina. El tratamiento con dabrafenib y trametinib fue suspendido iniciándose corticoterapia tópica y sistémica, apreciándose una buena respuesta y recuperando una agudeza visual de 1,0 en ambos ojos en 2 semanas. Discusión: El dabrafenib y el trametinib pueden producir una severa panuveítis. El tratamiento con corticoides y la suspensión de dabrafenib y trametinib consiguió controlar la uveítis, con recuperación de la agudeza visual, rápidamente. Los oftalmólogos debemos conocer este tipo de toxicidad debido al creciente uso de estos fármacos

Case report: The case is presented of a 39-year-old woman with metastatic melanoma treated with dabrafenib and trametinib. She presented with a severe acute panuveitis with granulomatous anterior uveitis, vitritis, and multiple serous retinal detachments. Dabrafenib and trametinib were suspended, and treatment with a systemic and topical corticosteroid was started. A good response was obtained, with a recovery of visual acuity of 1.0 in both eyes within two weeks. Discussion: Dabrafenib and trametinib can lead to severe uveitis. Treatment with corticosteroids and discontinuation of therapy with dabrafenib and trametinib led to an anatomical and functional improvement, and resolved the episode rapidly. Ophthalmologists must be aware of this toxicity, given the increasing use of those drugs

Protective role of downregulated MLK3 in myocardial adaptation to chronic hypoxia

A series of protective responses could be evoked to achieve compensatory adaptation once cardiomyocytes are subjected to chronic hypoxia. MLK3/JNK/c-jun signaling pathway was previously demonstrated to be involved in this process. In the present study, we aim to further examine the performance of MLK3 in hypoxic H9C2 cells and potential mechanism. Myocardial samples of patients with congenital heart disease (CHD) were collected. H9C2 cells were cultured in hypoxic conditions for various durations. MLK3 was silenced by transfection of shRNA to evaluate its role in cell viability. We found expression of MLK3 protein was lower in patients with cyanotic CHD. In hypoxic H9C2 cells, its expression was gradually decreased in a time-dependent manner. However, there was no significant difference about expression of MLK3 mRNA. According to the results of MTT, LDH, and TUNEL, faster cell growth curve, lower death rate, and less apoptotic cells could be observed in MLK-shRNA group compared with scramble-shRNA group. Silencing of MLK3 significantly reduced expression of cleaved caspase-3, cleaved PARP, Bad, and Bax, together with increased expression of Bcl-2 and ration of Bcl-2/Bax. Both ratio of phospho-JNK/total JNK and ratio of phospho-c-jun/total c-jun were significantly decreased once MLK3 was silenced. At various reoxygenation time, MLK3 shRNA could significantly promote cell survival and decrease cell death according to MTT and LDH. Our results suggested that chronic hypoxia could reduce MLK3 expression in a posttranscriptional regulatory manner. Downregulation of MLK3 protects H9C2 cells from hypoxia-induced apoptosis and H/R injury via blocking the activation of JNK and c-jun

Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management / Efectos cutáneos adversos de los nuevos tratamientos para melanoma: Clasificación y Tratamiento

Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient’s overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management

En la última década han aparecido nuevos tratamientos para el melanoma avanzado, como las terapias contra dianas como los inhibidores de BRAF o MEK, y las inmunoterapias como los anticuerpos contra CTLA-4 y PD1. Debido al uso cada vez más frecuente de estos tratamientos también han aparecido diversos efectos secundarios cutáneos, que van desde efectos graves y frecuentes como el desarrollo de carcinomas espinocelulares, a cambios cosméticos como el pelo rizado, o casos infrecuentes y graves de necrosis epidérmica tóxica. La detección y el tratamiento temprano de estos efectos adversos ayudará a los pacientes a recibir mejor tratamiento, a evitar el cese de la terapia antitumoral y a mejorar su calidad de vida. En esta revisión describiremos los efectos cutáneos adversos de los nuevos tratamientos contra el melanoma y su tratamiento

Actualización del tratamiento de las rasopatías / Update on the treatment of RASopathies

Introducción. El término «rasopatías» agrupa una serie de enfermedades que presentan mutaciones en genes que codifican las proteínas de la vía RAS/MAPK. Estas enfermedades incluyen la neurofibromatosis de tipo 1, el síndrome de Noonan, el síndrome de Legius, el síndrome LEOPARD, el síndrome de Costello y el síndrome cardiofaciocutáneo. La afectación de la vía RAS/MAPK no sólo aumenta la predisposición a desarrollar tumores, sino que también determina la presencia de anomalías fenotípicas y alteraciones en los procesos de aprendizaje. Objetivo. Revisar el papel del uso de estrategias terapéuticas con mecanismos de acción selectivo en las rasopatías. Desarrollo. El hecho de que la vía RAS participe en un tercio de las neoplasias ha motivado el desarrollo y el estudio de distintos fármacos a este nivel. Algunos de estos fármacos han sido probados en las rasopatías, principalmente en la neurofibromatosis de tipo 1. Analizamos el uso de distintos tratamientos antidiana: fármacos que actúan en los receptores de membrana, como los inhibidores de la tirosincinasa, en la vía mTOR o los inhibidores de MEK. Existe un potencial beneficio de estos últimos en estudios recientes realizados en distintas rasopatías. Conclusiones. Actualmente, gracias a los resultados de los primeros trabajos desarrollados con inhibidor de MEK basados principalmente en modelos animales, se están realizando múltiples ensayos clínicos prometedores (AU)

Introduction. The term «RASopathies» covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes. Aim. To review the use of therapeutic strategies with mechanisms that have a selective action on RASopathies. Development. The fact that the RAS pathway is involved in a third of all neoplasms has led to the development and study of different drugs at this level. Some of these pharmaceutical agents have been tested in RASopathies, mainly in neurofibromatosis type 1. Here we analyse the use of different antitarget treatments: drugs that act on the membrane receptors, such as tyrosine kinase inhibitors, in the mTOR pathway or MEK inhibitors. These latter have shown potential benefits in recent studies conducted on different RASopathies. Conclusions. Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out (AU)

Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data

BACKGROUND: We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma. METHODS: Eligible studies included prospective studies evaluating doublet regimens versus BRAF-inhibitor monotherapy for the management of BRAF-mutant advanced melanoma. RESULTS: Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001]. CONCLUSIONS: Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities

No disponible