RESUMO
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor X Retinoide gama/antagonistas & inibidores , Animais , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , Masculino , Melanoma/metabolismo , Melanoma/patologia , Camundongos SCID , Mutação , Neoplasia Residual/metabolismo , Neoplasia Residual/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Focal amplifications of chromosome 3p13-3p14 occur in about 10% of melanomas and are associated with a poor prognosis. The melanoma-specific oncogene MITF resides at the epicentre of this amplicon. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA (lncRNA) gene SAMMSON is consistently co-gained with MITF. In addition, SAMMSON is a target of the lineage-specific transcription factor SOX10 and its expression is detectable in more than 90% of human melanomas. Whereas exogenous SAMMSON increases the clonogenic potential in trans, SAMMSON knockdown drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state and BRAF, NRAS or TP53 mutational status. Moreover, SAMMSON targeting sensitizes melanoma to MAPK-targeting therapeutics both in vitro and in patient-derived xenograft models. Mechanistically, SAMMSON interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that silencing of the lineage addiction oncogene SAMMSON disrupts vital mitochondrial functions in a cancer-cell-specific manner; this silencing is therefore expected to deliver highly effective and tissue-restricted anti-melanoma therapeutic responses.
Assuntos
Melanoma/genética , Melanoma/patologia , Oncogenes/genética , RNA Longo não Codificante/genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Proteínas de Transporte , Linhagem da Célula , Proliferação de Células , Sobrevivência Celular , Cromossomos Humanos Par 3/genética , Células Clonais/metabolismo , Células Clonais/patologia , Feminino , Amplificação de Genes/genética , Técnicas de Silenciamento de Genes , Humanos , Melanoma/terapia , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , RNA Longo não Codificante/uso terapêutico , Fatores de Transcrição SOXE/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. METHODS: We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. RESULTS: 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). CONCLUSIONS: Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.
Assuntos
Hepatite , Inibidores de Checkpoint Imunológico , Imunoterapia , Melanoma , Nefrite , Pneumonia , Humanos , Anticorpos Monoclonais/uso terapêutico , Hepatite/etiologia , Imunoterapia/efeitos adversos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Nefrite/complicações , Nefrite/tratamento farmacológico , Pneumonia/etiologia , Estações do Ano , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
BACKGROUND: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. METHODS: Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. RESULTS: We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. CONCLUSIONS: We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.
Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Lipídeos de Membrana/farmacologia , Lipídeos de Membrana/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos AntineoplásicosRESUMO
Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.
Assuntos
Neoplasias Encefálicas , Melanoma , Humanos , Melanoma/patologia , Mutação , Evolução Molecular , DNARESUMO
Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.
Assuntos
COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , Neoplasias Hematológicas/tratamento farmacológicoRESUMO
INTRODUCTION: Patients with metastatic soft-tissue sarcoma generally have a poor prognosis. Although chemotherapy is associated with improved overall survival in these patients, long-term benefit is rare. CASE REPORT: We report on 2 patients with metastatic soft-tissue sarcoma who achieved a complete response to chemotherapy, without any local therapy, and had no signs of disease progression more than a decade after discontinuing treatment. CONCLUSION: These observations highlight the potential benefit of chemotherapy in a disease that is often considered to be poorly responsive to this treatment. These observations support further efforts to identify factors to guide patient selection and treatment optimization.
Assuntos
Segunda Neoplasia Primária , Sarcoma , Neoplasias de Tecidos Moles , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Prognóstico , Neoplasias de Tecidos Moles/patologiaRESUMO
Cancer is an evolutionary process that is characterized by the emergence of multiple genetically distinct populations or clones within the primary tumor. Intratumor heterogeneity provides a substrate for the selection of adaptive clones, such as those that lead to metastasis. Comparative molecular studies of primary tumors and metastases have identified distinct genomic features associated with the development of metastases. In this review, we discuss how these insights could inform clinical decision-making and uncover rational antimetastasis treatment strategies.
Assuntos
Neoplasias , Evolução Molecular , Heterogeneidade Genética , Humanos , Mutação , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologiaRESUMO
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Neoplasias , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Estudos Clínicos como Assunto , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2RESUMO
PURPOSE: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Melanoma/tratamento farmacológico , Melanoma/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Imidazóis/farmacologia , Melanoma/patologia , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Crista Neural/patologia , Oximas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. METHODS: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. FINDINGS: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. INTERPRETATION: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.
Assuntos
COVID-19/epidemiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , COVID-19/virologia , Estudos de Coortes , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificaçãoRESUMO
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Transativadores/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Medula Óssea/patologia , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Transativadores/genética , Transativadores/metabolismo , Transcrição Gênica/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Neurofibromatosis 1 (NF1) leads to the development of benign and malignant peripheral nerve sheath tumors (MPNST). MPNST have been described to develop in preexisting benign plexiform neurofibromas (PN) and have a poor prognosis. Atypical neurofibromas (ANF) were recently described as precursor lesions for MPNST, making early detection and management of ANF a possible strategy to prevent MPNST. We aimed to clinically characterize ANF and identify management approaches. Methods: We analyzed clinical, imaging, and pathology findings of all patients with NF1 and ANF at 3 institutions. Results: Sixty-three patients had 76 ANF (32M/31F; median age 27.1 y). On MRI, most ANF appeared as distinct nodular lesions and were 18F-fluorodeoxyglucose (FDG) avid. Forty-six ANF were associated with pain, 19 with motor weakness, 45 were palpable or visible, and 13 had no clinical signs. Completely resected ANF (N = 57) have not recurred (median follow-up, 4.1 y; range, 0-14 y). Four ANF transformed into MPNST and 17 patients had a history of MPNST in a different location than was their ANF. Conclusions: Growth of distinct nodular lesions, pain, and FDG-PET avidity should raise concern for ANF in NF1. Patients with ANF are at greater risk for development of MPNST. Complete resection of ANF may prevent development of MPNST.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neurofibroma/patologia , Neurofibromatose 1/patologia , Neurofibrossarcoma/patologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibroma/complicações , Neurofibroma/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/etiologia , Neurofibrossarcoma/diagnóstico por imagem , Neurofibrossarcoma/etiologia , Prognóstico , Adulto JovemRESUMO
Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly, pharmacological SREBP-1 inhibition sensitizes BRAFV600E-mutant therapy-resistant melanoma to BRAFV600E inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together, these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Lipogênese/genética , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Melanócitos , Melanoma/genética , Camundongos , Camundongos Nus , Camundongos SCID , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridinas/farmacologia , Transdução de Sinais/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Tiazóis/farmacologia , Vemurafenib , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/genética , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazóis/farmacologia , Células MCF-7 , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Mutação , Oximas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Fatores de Transcrição , Carga Tumoral/efeitos dos fármacos , Vemurafenib/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib, three patients achieved a partial response and one patient achieved a complete response. Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Oximas/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway. This highlights the importance of using tests that detect both V600E/K and non-V600E/K BRAF mutations to keep open the possibility of treatment with targeted therapy in patients with uncommon, yet potentially actionable, BRAF exon 15 mutations.
Assuntos
Éxons , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Intervalo Livre de Doença , Humanos , Masculino , Melanoma/enzimologia , Melanoma/patologia , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologiaRESUMO
Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma.