Sujet(s)
Adalimumab , Protéines proto-oncogènes B-raf , Syndrome uvéo-méningo-encéphalique , Humains , Adalimumab/usage thérapeutique , Adalimumab/effets indésirables , Syndrome uvéo-méningo-encéphalique/traitement médicamenteux , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Résistance aux substances , Femelle , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/usage thérapeutique , Mâle , Anti-inflammatoires/usage thérapeutique , Anti-inflammatoires/effets indésirables , Adulte d'âge moyen , Sulfonamides/usage thérapeutique , Sulfonamides/effets indésirablesRÉSUMÉ
BACKGROUND/AIM: Uveal melanoma (UM) represents a prevailing primary intraocular malignancy, with a limited median overall survival among metastatic patients, and most tumors lack RAF/RAS mutations. The pan-RAF inhibitor LY3009120 has demonstrated valuable anti-tumor effects in a wide range of RAF/RASmut and wild-type (WT) tumor models. This study aimed to evaluate the antitumor effect of LY3009120 on 92-1 UM cell line. MATERIALS AND METHODS: The effect of the pan-RAF inhibitor LY3009120 on cell proliferation, metabolic activity, biomass, early and late apoptosis/necrosis, and morphology was characterized in vitro (0.1-5 µM for 48 h/72 h). Furthermore, targeted panel sequencing was used to characterize the mutational landscape of the human 92-1 UM cell line. RESULTS: LY3009120 showed a significant concentration-dependent anti-proliferative effect on 92-1 cells. Cell proliferation and viability were significantly reduced at the lowest effective concentration of 0.5 µM (at 48 and 72 h, p<0.001). Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in 92-1 cells at 5 µM. Except for TP53, NGS showed that all 49 additional analysed genes (Oncomine myeloid panel) of 92-1 were wild-type, including BRAF, NRAS, and KRAS. CONCLUSION: The pan-RAF inhibitor LY3009120 demonstrated a significant anti-tumor effect on human UM cell line 92-1 independent of the molecular BRAF and RAS mutational status.
Sujet(s)
Apoptose , Prolifération cellulaire , Mélanome , Tumeurs de l'uvée , Humains , Tumeurs de l'uvée/traitement médicamenteux , Tumeurs de l'uvée/anatomopathologie , Tumeurs de l'uvée/génétique , Mélanome/traitement médicamenteux , Mélanome/anatomopathologie , Mélanome/génétique , Mélanome/métabolisme , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Mutation , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Survie cellulaire/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Phénylurées/pharmacologie , PyrimidinesRÉSUMÉ
BACKGROUND: BRAF (v-raf murine sarcoma viral oncogene homolog B1)/MEK (mitogen-activated protein kinase kinase) inhibitors are used for melanoma treatment. Unfortunately, patients treated with this combined therapy develop resistance to treatment quite quickly, but the mechanisms underlying this phenomenon are not yet fully understood. Here, we report and characterize two melanoma cell lines (WM9 and Hs294T) resistant to BRAF (vemurafenib) and MEK (cobimetinib) inhibitors. METHODS: Cell viability was assessed via the XTT test. The level of selected proteins as well as activation of signaling pathways were evaluated using Western blotting. The expression of the chosen genes was assessed by RT-PCR. The distribution of cell cycle phases was analyzed by flow cytometry, and confocal microscopy was used to take photos of spheroids. The composition of cytokines secreted by cells was determined using a human cytokine array. RESULTS: The resistant cells had increased survival and activation of ERK kinase in the presence of BRAF/MEK inhibitors. The IC50 values for these cells were over 1000 times higher than for controls. Resistant cells also exhibited elevated activation of AKT, p38, and JNK signaling pathways with increased expression of EGFR, ErbB2, MET, and PDGFRß receptors as well as reduced expression of ErbB3 receptor. Furthermore, these cells demonstrated increased expression of genes encoding proteins involved in drug transport and metabolism. Resistant cells also exhibited features of epithelial-mesenchymal transition and cancer stem cells as well as reduced proliferation rate and elevated cytokine secretion. CONCLUSIONS: In summary, this work describes BRAF/MEK-inhibitor-resistant melanoma cells, allowing for better understanding the underlying mechanisms of resistance. The results may thus contribute to the development of new, more effective therapeutic strategies.
Sujet(s)
Azétidines , Résistance aux médicaments antinéoplasiques , Mélanome , Pipéridines , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Vémurafénib , Humains , Mélanome/anatomopathologie , Mélanome/génétique , Mélanome/traitement médicamenteux , Mélanome/métabolisme , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/métabolisme , Azétidines/pharmacologie , Lignée cellulaire tumorale , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Inhibiteurs de protéines kinases/pharmacologie , Pipéridines/pharmacologie , Vémurafénib/pharmacologie , Mitogen-Activated Protein Kinase Kinases/antagonistes et inhibiteurs , Mitogen-Activated Protein Kinase Kinases/métabolisme , Survie cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.
Sujet(s)
Craniopharyngiome , Oximes , Tumeurs de l'hypophyse , Protéines proto-oncogènes B-raf , Pyridones , Pyrimidinones , Humains , Femelle , Mâle , Adulte d'âge moyen , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Adulte , Études rétrospectives , Craniopharyngiome/traitement médicamenteux , Pyridones/usage thérapeutique , Pyridones/administration et posologie , Pyridones/effets indésirables , Sujet âgé , Tumeurs de l'hypophyse/traitement médicamenteux , Pyrimidinones/usage thérapeutique , Pyrimidinones/administration et posologie , Pyrimidinones/effets indésirables , Oximes/usage thérapeutique , Oximes/administration et posologie , Oximes/effets indésirables , Études de cohortes , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/effets indésirables , Thérapie moléculaire ciblée/méthodes , Imidazoles/usage thérapeutique , Imidazoles/administration et posologie , Imidazoles/effets indésirables , Résultat thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutiqueRÉSUMÉ
The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.
Sujet(s)
Adénocarcinome pulmonaire , Résistance aux médicaments antinéoplasiques , Inhibiteurs de désacétylase d'histone , Tumeurs du poumon , Phospholipid hydroperoxide glutathione peroxidase , Protéines proto-oncogènes B-raf , Humains , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/anatomopathologie , Adénocarcinome pulmonaire/métabolisme , Phospholipid hydroperoxide glutathione peroxidase/métabolisme , Phospholipid hydroperoxide glutathione peroxidase/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Lignée cellulaire tumorale , Animaux , Inhibiteurs de désacétylase d'histone/pharmacologie , Ferroptose/effets des médicaments et des substances chimiques , Ferroptose/génétique , Souris , Stress oxydatif/effets des médicaments et des substances chimiques , Oximes/pharmacologie , Imidazoles/pharmacologie , Pyridones/pharmacologie , Pyrimidinones/pharmacologie , Peroxydation lipidique/effets des médicaments et des substances chimiques , Mutation/génétique , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
Sujet(s)
Antinéoplasiques , Benzothiazoles , Prolifération cellulaire , Simulation de docking moléculaire , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Thiadiazoles , Récepteur-2 au facteur croissance endothéliale vasculaire , Récepteur-2 au facteur croissance endothéliale vasculaire/antagonistes et inhibiteurs , Récepteur-2 au facteur croissance endothéliale vasculaire/métabolisme , Humains , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/synthèse chimique , Benzothiazoles/composition chimique , Benzothiazoles/pharmacologie , Benzothiazoles/synthèse chimique , Thiadiazoles/composition chimique , Thiadiazoles/pharmacologie , Thiadiazoles/synthèse chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Conception de médicament , Relation structure-activité , Sorafénib/pharmacologie , Sorafénib/composition chimique , Structure moléculaire , Simulation numérique , Tests de criblage d'agents antitumorauxRÉSUMÉ
The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.
Sujet(s)
Mélanome , Métabolomique , Inhibiteurs de protéines kinases , Mélanome/métabolisme , Mélanome/traitement médicamenteux , Mélanome/anatomopathologie , Humains , Métabolomique/méthodes , Lignée cellulaire tumorale , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Spectroscopie par résonance magnétique/méthodes , Mitogen-Activated Protein Kinases/métabolisme , Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Spectroscopie par résonance magnétique du proton/méthodesRÉSUMÉ
Metastatic melanoma is among the most enigmatic advanced cancers to clinically manage despite immense progress in the way of available therapeutic options and historic decreases in the melanoma mortality rate. Most patients with metastatic melanoma treated with modern targeted therapies (for example, BRAFV600E/K inhibitors) and/or immune checkpoint blockade (for example, anti-programmed death 1 therapy) will progress, owing to profound tumor cell plasticity fueled by genetic and nongenetic mechanisms and dichotomous host microenvironmental influences. Here we discuss the determinants of tumor heterogeneity, mechanisms of therapy resistance and effective therapy regimens that hold curative promise.
Sujet(s)
Résistance aux médicaments antinéoplasiques , Mélanome , Humains , Mélanome/traitement médicamenteux , Mélanome/génétique , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Thérapie moléculaire ciblée/méthodes , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/génétiqueRÉSUMÉ
The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Tumeurs colorectales , Inhibiteurs de points de contrôle immunitaires , Oxaliplatine , Protéines proto-oncogènes B-raf , Humains , Oxaliplatine/usage thérapeutique , Oxaliplatine/administration et posologie , Femelle , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Mutation , Instabilité des microsatellites/effets des médicaments et des substances chimiques , Résultat thérapeutique , Sujet âgé de 80 ans ou plusRÉSUMÉ
BACKGROUND: BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. METHODS: CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. RESULTS: We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. CONCLUSIONS: Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.
Sujet(s)
Résistance aux médicaments antinéoplasiques , , Mélanome , Mutation , Facteurs initiation chaîne peptidique , Polyamines , Protéines proto-oncogènes B-raf , Protéines de liaison à l'ARN , Vémurafénib , Humains , Mélanome/traitement médicamenteux , Mélanome/génétique , Mélanome/métabolisme , Mélanome/anatomopathologie , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Résistance aux médicaments antinéoplasiques/génétique , Animaux , Polyamines/métabolisme , Souris , Facteurs initiation chaîne peptidique/métabolisme , Facteurs initiation chaîne peptidique/génétique , Lignée cellulaire tumorale , Protéines de liaison à l'ARN/métabolisme , Protéines de liaison à l'ARN/génétique , Vémurafénib/pharmacologie , Protéines proto-oncogènes c-myc/métabolisme , Protéines proto-oncogènes c-myc/génétique , Tests d'activité antitumorale sur modèle de xénogreffe , Systèmes CRISPR-Cas , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Lysine/analogues et dérivésRÉSUMÉ
Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.
Sujet(s)
Mélanome , Protéines proto-oncogènes B-raf , Humains , Mélanome/traitement médicamenteux , Mélanome/métabolisme , Mélanome/génétique , Mélanome/anatomopathologie , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Mutation , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/anatomopathologie , Tumeurs cutanées/métabolisme , Tumeurs cutanées/génétique , Glycolyse/effets des médicaments et des substances chimiquesRÉSUMÉ
Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation and survival. BRAFV600E inhibitors like vemurafenib and dabrafenib have enhanced patient survival, yet drug resistance remains a significant challenge. We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. In BRAFV600E melanoma, ERK5 inhibition minimally affected viability compared to ERK1/2 inhibition. In vemurafenib-resistant cells, ERK5 inhibition alone didn't impact viability or restore drug sensitivity to vemurafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma.
Sujet(s)
Résistance aux médicaments antinéoplasiques , Imidazoles , Mélanome , Mitogen-Activated Protein Kinase 7 , Oximes , Protéines proto-oncogènes B-raf , Vémurafénib , Oximes/pharmacologie , Humains , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Mélanome/traitement médicamenteux , Mélanome/génétique , Mélanome/anatomopathologie , Mélanome/métabolisme , Imidazoles/pharmacologie , Vémurafénib/pharmacologie , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Mitogen-Activated Protein Kinase 7/métabolisme , Mitogen-Activated Protein Kinase 7/génétique , Indoles/pharmacologie , Sulfonamides/pharmacologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/génétique , Tumeurs cutanées/anatomopathologie , Tumeurs cutanées/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , MutationRÉSUMÉ
Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).
Sujet(s)
Antinéoplasiques , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/métabolisme , Humains , Animaux , Souris , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Lignée cellulaire tumorale , Femelle , Barrière hémato-encéphalique/métabolisme , Encéphale/métabolisme , Mélanome/traitement médicamenteux , Mélanome/anatomopathologie , Relation structure-activité , Rats , Souris nude , Tests d'activité antitumorale sur modèle de xénogreffe , MâleRÉSUMÉ
Tovorafenib (OJEMDA™) is a once-weekly oral, selective, brain-penetrant, type II RAF kinase inhibitor being developed by Day One Biopharmaceuticals, Inc., under a license from Takeda Oncology, for the treatment of paediatric low-grade glioma (pLGG) and solid tumours. Most pLGGs harbour alterations in the MAPK pathway, such as a BRAF mutation or BRAF fusion, which result in aberrant intracellular signalling. Tovorafenib is an inhibitor of mutant BRAF V600E, wild-type BRAF and wild-type CRAF kinases and BRAF fusions. In April 2024, tovorafenib received its first approval in the USA for the treatment of patients aged ≥ 6 months with relapsed or refractory pLGGs harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation. It received accelerated approval for this indication based on the response rate and duration of response achieved in this population in the ongoing, pivotal, phase 2 FIREFLY-1 study. Clinical development of tovorafenib is underway in numerous countries worldwide. This article summarizes the milestones in the development of tovorafenib leading to this first approval for relapsed or refractory pLGG with an activating BRAF alteration.
Sujet(s)
Agrément de médicaments , Gliome , Protéines proto-oncogènes B-raf , Humains , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Gliome/traitement médicamenteux , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologie , Enfant , Tumeurs du cerveau/traitement médicamenteux , Mutation , Phénylurées/usage thérapeutique , Phénylurées/pharmacologieRÉSUMÉ
We present a case of a 75-year-old male patient who experienced a severe exacerbation of his Kaposi sarcoma lesions, which have remained clinically stable for a year, following treatment with BRAF/mitogen-activated protein kinase inhibitors for his coexisting melanoma. In this case, we present the possibility that BRAF/MEK inhibition may be mechanistically associated with the progression of Kaposi sarcoma and briefly discuss the potential mechanisms behind this phenomenon.
Sujet(s)
Mélanome , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Sarcome de Kaposi , Tumeurs cutanées , Humains , Mâle , Sujet âgé , Sarcome de Kaposi/traitement médicamenteux , Mélanome/traitement médicamenteux , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/anatomopathologie , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirablesRÉSUMÉ
INTRODUCTION: BRAF V600E substitution predicts sensitivity of a cancer to BRAF inhibitor therapy. The mutation is rarely found in soft-tissue sarcomas. Here we describe a case of undifferentiated spindle cell sarcoma showing primary insensitivity to standard chemotherapy and pronounced but non-sustained response to BRAF/MEK inhibitors at recurrence. CASE PRESENTATION: A 13-year-old girl was diagnosed with low-grade spindle cell sarcoma of pelvic localization, BRAF exon 15 double-mutated: c.1799T>A p.V600E and c.1819T>A p.S607T in cis-position. The tumor showed resistance to CWS-based first-line chemotherapy and was treated surgically by radical resection. Seven months after surgery the patient developed metastatic relapse with abdominal carcinomatosis. Combined targeted therapy with BRAF/MEK inhibitors afforded complete response in 1 month and was continued, though complicated by severe side effects (fever, rash) necessitating 1-2 week toxicity breaks. After 4 months from commencement the disease recurred and anti-BRAF/MEK regimen consolidation was unsuccessful. Intensive salvation chemotherapy was ineffective. Empirical immunotherapy afforded a transient partial response giving way to fatal progression with massive, abdominal cocoon-complicated peritoneal carcinomatosis. CONCLUSION: This is the first report of spindle cell sarcoma BRAF V600E/S607T double-mutated, responding to a combination of B-Raf and MEK inhibitors. Despite the low histological grade and radical surgical treatment of the tumor at primary manifestation, the disease had aggressive clinical course and the response to BRAF/MEK targeted therapy at recurrence was complete but nondurable. Empirical use of pembrolizumab provided no unambiguous evidence on the clinical relevance of immunotherapy in protein kinase -rearranged spindle cell tumors.
Sujet(s)
Exons , Mutation , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Sarcomes , Humains , Femelle , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Adolescent , Sarcomes/génétique , Sarcomes/traitement médicamenteux , Sarcomes/anatomopathologie , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Mitogen-Activated Protein Kinase Kinases/antagonistes et inhibiteursRÉSUMÉ
Activating mutations in the mitogen-activated protein kinase (MAPK) pathway represent driver alterations governing tumorigenesis, metastasis, and therapy resistance. MAPK activation predominantly occurs through genomic alterations in RAS and BRAF. BRAF is an effector kinase that functions downstream of RAS and propagates this oncogenic activity through MEK and ERK. Across cancers, BRAF alterations include gain-of-function mutations, copy-number alterations, and structural rearrangements. In cancer patients, BRAF-targeting precision therapeutics are effective against Class I BRAF alterations (p.V600 hotspot mutations) in tumors such as melanomas, thyroid cancers, and colorectal cancers. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in some cancers. Here we discuss the diverse forms of BRAF alterations found in human cancers and the strategies to inhibit them in patients harboring cancers of distinct origins.
Sujet(s)
Thérapie moléculaire ciblée , Tumeurs , Inhibiteurs de protéines kinases , Protéines proto-oncogènes B-raf , Humains , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/métabolisme , Tumeurs/génétique , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologie , Tumeurs/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Mutation , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Animaux , Système de signalisation des MAP kinases/génétiqueRÉSUMÉ
Metastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti-resistance agents to current treatment protocols can potentially improve clinical responses. Myocardin-related transcription factor (MRTF) is a transcriptional coactivator whose activity is indirectly regulated by actin and the Rho family of GTPases. We previously demonstrated that development of BRAF inhibitor (BRAFi) resistance frequently activates the Rho/MRTF pathway in human and mouse BRAFV600E melanomas. In clinical trials, pretreatment with BRAFi reduces the benefit of immune therapies. We aimed to test the efficacy of concurrent treatment with our MRTF pathway inhibitor CCG-257081 and anti-PD1 in vivo and to examine its effects on the melanoma immune microenvironment. Because MRTF pathway activation upregulates the expression of immune checkpoint inhibitor genes/proteins, we asked whether CCG-257081 can improve the response to immune checkpoint blockade. CCG-257081 reduced the expression of PDL1 in BRAFi-resistant melanoma cells and decreased surface PDL1 levels on both BRAFi-sensitive and -resistant melanoma cells. Using our recently described murine vemurafenib-resistant melanoma model, we found that CCG-257081, in combination with anti-PD1 immune therapy, reduced tumor growth and increased survival. Moreover, anti-PD1/CCG-257081 co-treatment increased infiltration of CD8+ T cells and B cells into the tumor microenvironment and reduced tumor-associated macrophages. Here, we propose CCG-257081 as an anti-resistance and immune therapy-enhancing anti-melanoma agent.
Sujet(s)
Antigène CD274 , Résistance aux médicaments antinéoplasiques , Inhibiteurs de points de contrôle immunitaires , Mélanome , Protéines proto-oncogènes B-raf , Tumeurs cutanées , Microenvironnement tumoral , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Animaux , Mélanome/traitement médicamenteux , Mélanome/métabolisme , Mélanome/génétique , Mélanome/anatomopathologie , Souris , Humains , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/métabolisme , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Tumeurs cutanées/traitement médicamenteux , Tumeurs cutanées/anatomopathologie , Tumeurs cutanées/génétique , Tumeurs cutanées/métabolisme , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/métabolisme , Transactivateurs/métabolisme , Transactivateurs/génétique , Femelle , Transduction du signal/effets des médicaments et des substances chimiques , Protéines G rho/métabolismeRÉSUMÉ
Melanoma cells express high levels of CD73 that produce extracellular immunosuppressive adenosine. Changes in the CD73 expression occur in response to tumor environmental factors, contributing to tumor phenotype plasticity and therapeutic resistance. Previously, we have observed that CD73 expression can be up-regulated on the surface of melanoma cells in response to nutritional stress. Here, we explore the mechanism by which melanoma cells release soluble CD73 under low nutrient availability and whether this might be affected by agents targeting the proto-oncogene B-Raf (BRAF). We found that starved melanoma cells can release high levels of CD73, able to convert AMP into adenosine, and this activity is abrogated by selective CD73 inhibitors, APCP or PSB-12489. The release of CD73 from melanoma cells is mediated by the matrix metalloproteinase MMP-9. Indeed, MMP-9 inhibitors significantly reduce the levels of CD73 released from the cells, while its surface levels increase. Of relevance, melanoma cells, harboring an activating BRAF mutation, upon treatment with dabrafenib or vemurafenib, show a strong reduction of CD73 cell expression and reduced levels of CD73 released into the extracellular space. Conversely, melanoma cells resistant to dabrafenib show high expression of membrane-bound CD73 and soluble CD73 released into the culture medium. In summary, our data indicate that CD73 is released from melanoma cells. The expression of CD73 is associated with response to BRAF inhibitors. Melanoma cells developing resistance to dabrafenib show increased expression of CD73, including soluble CD73 released from cells, suggesting that CD73 is involved in acquiring resistance to treatment.
Sujet(s)
5'-Nucleotidase , Résistance aux médicaments antinéoplasiques , Mélanome , Proto-oncogène Mas , Protéines proto-oncogènes B-raf , Vémurafénib , Mélanome/traitement médicamenteux , Mélanome/génétique , Mélanome/métabolisme , Mélanome/anatomopathologie , Humains , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes B-raf/génétique , 5'-Nucleotidase/métabolisme , 5'-Nucleotidase/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Vémurafénib/pharmacologie , Oximes/pharmacologie , Matrix metalloproteinase 9/métabolisme , Imidazoles/pharmacologie , Inhibiteurs de protéines kinases/pharmacologie , Protéines liées au GPI/métabolisme , Protéines liées au GPI/génétiqueRÉSUMÉ
PURPOSE OF REVIEW: Given the rapid development of multiple targeted and immune therapies for patients with advanced melanoma, it can be challenging to select a therapy based on currently available data. This review aims to provide an overview of frontline options for metastatic melanoma, with practical guidance for selecting a treatment regimen. RECENT FINDINGS: Recently reported data from randomized trials suggests that the majority of patients with unresectable melanoma should receive a PD-1 checkpoint inhibitor as part of their first line therapy, irrespective of BRAF mutation status. Additional data also suggests that combination immunotherapies result in improved outcomes compared to single agent, albeit at the cost of increased toxicity, though to date no biomarker exists to help guide treatment selection. As the number therapeutic options continue to grow for patients with advanced melanoma, there is likely to be a continued focus on combination strategies. Defining the optimal treatment approach in order to maximize efficacy while minimizing toxicity remains an area of active investigation.