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1.
Mol Oncol ; 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34632715

RESUMO

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.

2.
Science ; 373(6561): eabj0486, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529467
3.
Cancer Res ; 81(21): 5572-5581, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34518211

RESUMO

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.

4.
Cancers (Basel) ; 13(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34359705

RESUMO

Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a "drop-out" loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings.

5.
EMBO Mol Med ; 13(7): e12872, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34062049

RESUMO

Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains the aggressiveness of HNSCC cells and protects from RT-induced cell death. Mechanistically, by targeting KLF5, miR-9 regulates the expression of the transcription factor Sp1 that, in turn, stimulates tumor growth and confers resistance to RT+CTX in vitro and in vivo. Intriguingly, high miR-9 levels have no effect on the sensitivity of HNSCC cells to cisplatin. In primary HNSCC, miR-9 expression correlated with Sp1 mRNA levels and high miR-9 expression predicted poor prognosis in patients treated with RT+CTX. Overall, we have discovered a new signaling axis linking EGFR activation to Sp1 expression that dictates the response to combination treatments in HNSCC. We propose that miR-9 may represent a valuable biomarker to select which HNSCC patients might benefit from RT+CTX therapy.


Assuntos
Neoplasias de Cabeça e Pescoço , MicroRNAs , Linhagem Celular Tumoral , Cetuximab/farmacologia , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
6.
Cancer Discov ; 11(11): 2904-2923, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34039636

RESUMO

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.This article is highlighted in the In This Issue feature, p. 2659.

7.
Gastroenterology ; 161(1): 196-210, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33745946

RESUMO

BACKGROUND & AIMS: Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS: Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS: Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Carioferinas/antagonistas & inibidores , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Bases de Dados Genéticas , Células HCT116 , Células HT29 , Humanos , Indóis/administração & dosagem , Carioferinas/metabolismo , Camundongos , Morfolinas/administração & dosagem , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptores Citoplasmáticos e Nucleares/metabolismo , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Res ; 81(2): 332-343, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33158812

RESUMO

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment. SIGNIFICANCE: This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Resorcinóis/farmacologia , Fatores de Transcrição/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Res ; 80(21): 4840-4853, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32928921

RESUMO

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Experimentais/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Neoplasias Experimentais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Med Chem ; 63(17): 9888-9911, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787110

RESUMO

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.


Assuntos
Antineoplásicos/uso terapêutico , Benzotiazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Células THP-1 , Macrófagos Associados a Tumor/efeitos dos fármacos
11.
Cancer Res ; 79(21): 5612-5625, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492820

RESUMO

Mutated KRAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic KRAS are still under investigation or awaiting clinical approval. Using a specific KRAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic KRAS. We identified and validated decitabine, an FDA-approved drug, as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed KRAS dependency. Mechanistically, decitabine efficacy was linked to KRAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in KRAS-dependent tumors cells. These findings also showed that gene signatures related to KRAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of patients with KRAS-mutated pancreatic cancer. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant KRAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease. SIGNIFICANCE: Decitabine is a promising drug for cancer cells dependent on RAS signaling.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Decitabina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Reposicionamento de Medicamentos/métodos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
12.
Cancers (Basel) ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500168

RESUMO

Our poor understanding of the intricate biology of cancer and the limited availability of preclinical models that faithfully recapitulate the complexity of tumors are primary contributors to the high failure rate of novel therapeutics in oncology clinical studies. To address this need, patient-derived xenograft (PDX) platforms have been widely deployed and have reached a point of development where we can critically review their utility to model and interrogate relevant clinical scenarios, including tumor heterogeneity and clonal evolution, contributions of the tumor microenvironment, identification of novel drugs and biomarkers, and mechanisms of drug resistance. Colorectal cancer (CRC) constitutes a unique case to illustrate clinical perspectives revealed by PDX studies, as they overcome limitations intrinsic to conventional ex vivo models. Furthermore, the success of molecularly annotated "Avatar" models for co-clinical trials in other diseases suggests that this approach may provide an additional opportunity to improve clinical decisions, including opportunities for precision targeted therapeutics, for patients with CRC in real time. Although critical weaknesses have been identified with regard to the ability of PDX models to predict clinical outcomes, for now, they are certainly the model of choice for preclinical studies in CRC. Ongoing multi-institutional efforts to develop and share large-scale, well-annotated PDX resources aim to maximize their translational potential. This review comprehensively surveys the current status of PDX models in translational CRC research and discusses the opportunities and considerations for future PDX development.

13.
JCI Insight ; 4(21)2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557131

RESUMO

Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Ductal Pancreático/genética , Oncogenes , Neoplasias Pancreáticas/genética , Fatores de Transcrição/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/patologia , Proteína Wnt-5a/genética
14.
Cancer ; 125(12): 1963-1972, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30835824

RESUMO

Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Assistência Centrada no Paciente , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Congressos como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Sociedades Científicas , Microambiente Tumoral
15.
Nature ; 568(7752): 410-414, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30918400

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2-4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and-in the case of PDAC-the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface-where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth-is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Pinocitose , Sindecana-1/metabolismo , Fatores de Ribosilação do ADP/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Masculino , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais
16.
Cancer Cell ; 35(2): 204-220.e9, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753823

RESUMO

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Proteostase , Tumor Rabdoide/metabolismo , Proteína SMARCB1/deficiência , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Proteassoma/farmacologia , Proteostase/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Transdução de Sinais , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Resposta a Proteínas não Dobradas
17.
Cell Rep ; 26(2): 469-482.e5, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625329

RESUMO

The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.


Assuntos
Fosforilação Oxidativa , Fosfogluconato Desidrogenase/genética , Mutações Sintéticas Letais , Animais , Linhagem Celular Tumoral , Feminino , Fumarato Hidratase/genética , Genômica/métodos , Glicólise , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Nus
18.
Cancer Discov ; 8(1): 17-19, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29311224

RESUMO

Adaptation and resistance to treatment are the results of a multitude of (epi)genetic events unmasked or directly triggered by therapies targeting the genetic driver(s) of a dominant cell population within a tumor mass. Rusan and colleagues report that drug-tolerant cells are sensitive to THZ1, a dual CDK7/12 inhibitor, which, by impairing the transcriptional machinery, can prevent cellular rewiring to survive therapeutic attack. Cancer Discov; 8(1); 17-9. ©2018 AACRSee related article by Rusan et al., p. 59.


Assuntos
Ecossistema , Neoplasias , Humanos
19.
Cancer Res ; 77(23): 6651-6666, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978636

RESUMO

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle-regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651-66. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Indóis/farmacologia , Neoplasias Renais/tratamento farmacológico , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Bevacizumab/farmacologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Neoplasias Renais/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Fosforilação , Receptores Proteína Tirosina Quinases/metabolismo , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cell ; 168(4): 579-583, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28187281

RESUMO

The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.


Assuntos
Antineoplásicos/economia , Custos de Medicamentos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Aprovação de Drogas , Custos de Medicamentos/legislação & jurisprudência , Descoberta de Drogas , Custos de Cuidados de Saúde , Humanos , Estados Unidos
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