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1.
Nature ; 603(7899): 166-173, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35197630

RESUMEN

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.


Asunto(s)
Antineoplásicos , Neoplasias del Colon , Neoplasias Pancreáticas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética
2.
Nature ; 568(7753): 511-516, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30971826

RESUMEN

Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.


Asunto(s)
Sistemas CRISPR-Cas/genética , Descubrimiento de Drogas/métodos , Edición Génica , Terapia Molecular Dirigida/métodos , Neoplasias/genética , Neoplasias/terapia , Animales , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Femenino , Genoma Humano/genética , Humanos , Ratones , Inestabilidad de Microsatélites , Trasplante de Neoplasias , Neoplasias/clasificación , Neoplasias/patología , Especificidad de Órganos , Reproducibilidad de los Resultados , Mutaciones Letales Sintéticas/genética , Síndrome de Werner/genética , Helicasa del Síndrome de Werner/genética
3.
Mol Ther ; 32(8): 2741-2761, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-38894542

RESUMEN

HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.


Asunto(s)
Neoplasias Colorrectales , Receptor ErbB-2 , Receptores Quiméricos de Antígenos , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Animales , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Ratones , Línea Celular Tumoral , Antígeno Carcinoembrionario/inmunología , Antígeno Carcinoembrionario/genética , Amplificación de Genes , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Inmunoterapia/métodos , Inmunoterapia Adoptiva/métodos , Modelos Animales de Enfermedad , Femenino
4.
Bioinformatics ; 39(5)2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37079732

RESUMEN

MOTIVATION: The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging. RESULTS: We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way. When used to analyze tumor growth kinetics over time in 1599 patient-derived xenograft growth curves from ovarian and colorectal cancers, CONNECTOR allowed the aggregation of time-series data through an unsupervised approach in informative clusters. We give a new perspective of mechanism interpretation, specifically, we define novel model aggregations and we identify unanticipated molecular associations with response to clinically approved therapies. AVAILABILITY AND IMPLEMENTATION: CONNECTOR is freely available under GNU GPL license at https://qbioturin.github.io/connector and https://doi.org/10.17504/protocols.io.8epv56e74g1b/v1.


Asunto(s)
Programas Informáticos , Humanos , Animales , Análisis por Conglomerados , Factores de Tiempo , Modelos Animales de Enfermedad , Medición de Riesgo
5.
Nat Rev Mol Cell Biol ; 11(12): 834-48, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21102609

RESUMEN

The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.


Asunto(s)
Estructuras Animales/fisiología , Crecimiento y Desarrollo/genética , Neoplasias/genética , Proteínas Proto-Oncogénicas c-met/fisiología , Regeneración/genética , Estructuras Animales/metabolismo , Animales , Crecimiento y Desarrollo/fisiología , Humanos , Modelos Biológicos , Modelos Moleculares , Neoplasias/etiología , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Regeneración/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología
6.
Nature ; 526(7572): 263-7, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26416732

RESUMEN

Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Genoma Humano/genética , Genómica , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Neoplasias Colorrectales/metabolismo , Variaciones en el Número de Copia de ADN/genética , Receptores ErbB/química , Receptores ErbB/genética , Exoma/genética , Femenino , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , MAP Quinasa Quinasa 1/genética , Ratones , Terapia Molecular Dirigida , Mutación/genética , Panitumumab , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Int J Cancer ; 147(10): 2891-2901, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32700762

RESUMEN

Antibodies targeting the human epidermal growth factor receptor (EGFR) are used for the treatment of RAS wild-type metastatic colorectal cancer. A significant proportion of patients remains unresponsive to this therapy. Here, we performed a reverse-phase protein array-based (phospho)protein analysis of 63 KRAS, NRAS, BRAF and PIK3CA wild-type metastatic CRC tumours. Responses of tumours to anti-EGFR therapy with cetuximab were recorded in patient-derived xenograft (PDX) models. Unsupervised hierarchical clustering of pretreatment tumour tissue identified three clusters, of which Cluster C3 was exclusively composed of responders. Clusters C1 and C2 exhibited mixed responses. None of the three protein clusters exhibited a significant correlation with transcriptome-based subtypes. Analysis of protein signatures across all PDXs identified 14 markers that discriminated cetuximab-sensitive and cetuximab-resistant tumours: PDK1 (S241), caspase-8, Shc (Y317), Stat3 (Y705), p27, GSK-3ß (S9), HER3, PKC-α (S657), EGFR (Y1068), Akt (S473), S6 ribosomal protein (S240/244), HER3 (Y1289), NF-κB-p65 (S536) and Gab-1 (Y627). Least absolute shrinkage and selection operator and binominal logistic regression analysis delivered refined protein signatures for predicting response to cetuximab. (Phospo-)protein analysis of matched pretreated and posttreated models furthermore showed significant reduction of Gab-1 (Y627) and GSK-3ß (S9) exclusively in responding models, suggesting novel targets for treatment.


Asunto(s)
Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Fosfoproteínas/metabolismo , Proteómica/métodos , Animales , Proliferación Celular/efectos de los fármacos , Cetuximab/farmacología , Fosfatidilinositol 3-Quinasa Clase I/genética , Análisis por Conglomerados , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , GTP Fosfohidrolasas/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratones , Fosfoproteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Aprendizaje Automático no Supervisado , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Mol Syst Biol ; 15(4): e8250, 2019 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-30979792

RESUMEN

Identifying hyperactive kinases in cancer is crucial for individualized treatment with specific inhibitors. Kinase activity can be discerned from global protein phosphorylation profiles obtained with mass spectrometry-based phosphoproteomics. A major challenge is to relate such profiles to specific hyperactive kinases fueling growth/progression of individual tumors. Hitherto, the focus has been on phosphorylation of either kinases or their substrates. Here, we combined label-free kinase-centric and substrate-centric information in an Integrative Inferred Kinase Activity (INKA) analysis. This multipronged, stringent analysis enables ranking of kinase activity and visualization of kinase-substrate networks in a single biological sample. To demonstrate utility, we analyzed (i) cancer cell lines with known oncogenes, (ii) cell lines in a differential setting (wild-type versus mutant, +/- drug), (iii) pre- and on-treatment tumor needle biopsies, (iv) cancer cell panel with available drug sensitivity data, and (v) patient-derived tumor xenografts with INKA-guided drug selection and testing. These analyses show superior performance of INKA over its components and substrate-based single-sample tool KARP, and underscore target potential of high-ranking kinases, encouraging further exploration of INKA's functional and clinical value.


Asunto(s)
Neoplasias/enzimología , Fosfotransferasas/análisis , Proteómica/métodos , Biología de Sistemas/métodos , Línea Celular Tumoral , Activación Enzimática , Humanos , Células K562 , Espectrometría de Masas , Fosfoproteínas/análisis
9.
Oncologist ; 24(10): 1395-1402, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30952821

RESUMEN

BACKGROUND: HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti-epidermal growth factor receptor (EGFR) treatment. SUBJECTS AND METHODS: Patients with KRAS exon 2 wild-type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2-negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti-EGFR treatment. RESULTS: From August 2012 to April 2018, a total of 100 HER2-positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild-type screened patients (6.7%). HER2-positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15-3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10-2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22-1.11; p = .088). HER2-positive patients who received treatment with anti-EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression-free survival, 5.7 months vs. 7 months, p = .087). CONCLUSION: Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy. IMPLICATIONS FOR PRACTICE: Patients with HER2-amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti-epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression-free survival in response to previous anti-EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2-targeted double blockade independently of previous anti-EGFR treatment.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Supervivencia sin Progresión , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Estudios Retrospectivos
10.
BMC Biol ; 14: 5, 2016 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-26787475

RESUMEN

BACKGROUND: Tankyrases are poly(adenosine diphosphate)-ribose polymerases that contribute to biological processes as diverse as modulation of Wnt signaling, telomere maintenance, vesicle trafficking, and microtubule-dependent spindle pole assembly during mitosis. At interphase, polarized reshaping of the microtubule network fosters oriented cell migration. This is attained by association of adenomatous polyposis coli with the plus end of microtubules at the cortex of cell membrane protrusions and microtubule-based centrosome reorientation towards the migrating front. RESULTS: Here we report a new function for tankyrases, namely, regulation of directional cell locomotion. Using a panel of lung cancer cell lines as a model system, we found that abrogation of tankyrase activity by two different, structurally unrelated small-molecule inhibitors (one introduced and characterized here for the first time) or by RNA interference-based genetic silencing weakened cell migration, invasion, and directional movement induced by the motogenic cytokine hepatocyte growth factor. Mechanistically, the anti-invasive outcome of tankyrase inhibition could be ascribed to sequential deterioration of the distinct events that govern cell directional sensing. In particular, tankyrase blockade negatively impacted (1) microtubule dynamic instability; (2) adenomatous polyposis coli plasma membrane targeting; and (3) centrosome reorientation. CONCLUSIONS: Collectively, these findings uncover an unanticipated role for tankyrases in influencing at multiple levels the interphase dynamics of the microtubule network and the subcellular distribution of related polarity signals. These results encourage the further exploration of tankyrase inhibitors as therapeutic tools to oppose dissemination and metastasis of cancer cells.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Pulmón/efectos de los fármacos , Tanquirasas/antagonistas & inhibidores , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Microtúbulos/metabolismo , Microtúbulos/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Interferencia de ARN , Tanquirasas/genética , Tanquirasas/metabolismo
11.
Lancet Oncol ; 17(6): 738-746, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27108243

RESUMEN

BACKGROUND: We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. METHODS: HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. FINDINGS: Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. INTERPRETATION: The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. FUNDING: Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores de Tumor , Codón/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Lapatinib , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Quinazolinas/administración & dosificación , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Terapia Recuperativa , Tasa de Supervivencia , Trastuzumab/administración & dosificación
12.
Biochim Biophys Acta ; 1846(1): 201-15, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25026313

RESUMEN

Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as "BRCAness") not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify "BRCAness" pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics.


Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Adenosina Difosfato Ribosa/metabolismo , Animales , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo
14.
Int J Cancer ; 135(10): 2305-16, 2014 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24706440

RESUMEN

MET is a master gene controlling a genetic program driving proliferation, apoptosis protection and invasion. The ROR1 pseudokinase acts as a MET substrate. However, its contribution to MET signaling and MET-dependent biological outcomes remains to be elucidated. By structure-function analysis of ROR1 mutants, we show that ROR1 encompasses two major substrate regions: one is located in the proline-rich domain and is directly phosphorylated by MET; the other resides in the pseudokinase domain and is phosphorylated through intermediate activation of SRC. Differential phosphorylation of these two regions dictates the execution of specific responses: phosphorylation of the ROR1 proline-rich domain by MET-but not phosphorylation of the pseudokinase domain by SRC-is necessary and sufficient to control MET-driven proliferation and protection from apoptosis. Differently, both the proline-rich and the pseudokinase domains mediate cell invasion. Consistent with the role of ROR1 in specifying the functional consequences of MET-dependent signals, ROR1 silencing leads to selective attenuation of only some of the signal transduction pathways sustained by MET. These data enlighten the so far elusive function(s) of pseudokinases and identify a mechanism of biological diversification, based on substrate specificity of oncogenic kinases.


Asunto(s)
Proteínas Proto-Oncogénicas c-met/metabolismo , Seudogenes/fisiología , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Animales , Apoptosis , Western Blotting , Células COS , Movimiento Celular , Proliferación Celular , Células Cultivadas , Chlorocebus aethiops , Humanos , Inmunoprecipitación , Lentivirus/genética , Fosforilación , Plásmidos/genética , Proteínas Proto-Oncogénicas c-met/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética
15.
Br J Haematol ; 164(6): 841-50, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24450886

RESUMEN

Abnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF mRNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET mRNA expression was higher in CD138(+) than in CD138(-) cells (median 76·90 vs. 11·24; P = 0·0009). Low MET mRNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56·10 vs. 134·83; P = 0·0006). After a median follow-up of 50 months, patients with high MET mRNA expression displayed a worse progression-free survival (PFS; P = 0·0029) and overall survival (OS; P = 0·0023) compared to those with low MET mRNA levels. Patients with both high MET mRNA expression and high ß2-microglobulin level (>5·5 mg/l) had further worse median PFS (P < 0·0001) and OS (P < 0·0001). Patients carrying 4 MET gene copies (8 out of 82, 9·8%) also had a short PFS. High MET mRNA expression identifies patients with dismal PFS and OS and the combination with high ß2-microglobulin further characterizes patients with worse outcome.


Asunto(s)
Factor de Crecimiento de Hepatocito/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Femenino , Factor de Crecimiento de Hepatocito/biosíntesis , Factor de Crecimiento de Hepatocito/sangre , Factor de Crecimiento de Hepatocito/genética , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo
16.
BMC Cancer ; 14: 918, 2014 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-25479910

RESUMEN

BACKGROUND: Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches. METHODS: We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models. RESULTS: We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways. CONCLUSIONS: These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Dioxoles/farmacología , Tetrahidroisoquinolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Neoplasias del Sistema Biliar/irrigación sanguínea , Neoplasias del Sistema Biliar/genética , Adhesión Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Reparación del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Histonas/metabolismo , Humanos , Interleucina-6/genética , Ratones , Ratones Endogámicos NOD , Neovascularización Patológica/tratamiento farmacológico , Fosforilación , Trabectedina , Proteína p53 Supresora de Tumor/metabolismo , Vía de Señalización Wnt/efectos de los fármacos
18.
J Exp Clin Cancer Res ; 43(1): 234, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164711

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide, with a survival rate near to 10% when diagnosed at an advanced stage. Hence, the identification of new molecular targets to design more selective and efficient therapies is urgently required. The Mitogen activated protein kinase kinase 3 (MKK3) is a dual-specificity threonine/tyrosine protein kinase that, activated in response to cellular stress and inflammatory stimuli, regulates a plethora of biological processes. Previous studies revealed novel MKK3 roles in supporting tumor malignancy, as its depletion induces autophagy and cell death in cancer lines of different tumor types, including CRC. Therefore, MKK3 may represent an interesting new therapeutic target in advanced CRC, however selective MKK3 inhibitors are currently not available. METHODS: The study involved transcriptomic based drug repurposing approach and confirmatory assays with CRC lines, primary colonocytes and a subset of CRC patient-derived organoids (PDO). Investigations in vitro and in vivo were addressed. RESULTS: The repurposing approach identified the multitargeted kinase inhibitor AT9283 as a putative compound with MKK3 depletion-mimicking activities. Indeed, AT9283 drops phospho- and total-MKK3 protein levels in tested CRC models. Likely the MKK3 silencing, AT9283 treatment: i) inhibited cell proliferation promoting autophagy and cell death in tested CRC lines and PDOs; ii) resulted well-tolerated by CCD-18Co colonocytes; iii) reduced cancer cell motility inhibiting CRC cell migration and invasion; iv) inhibited COLO205 xenograft tumor growth. Mechanistically, AT9283 abrogated MKK3 protein levels mainly through the inhibition of aurora kinase A (AURKA), impacting on MKK3/AURKA protein-protein interaction and protein stability therefore uncovering the relevance of MKK3/AURKA crosstalk in sustaining CRC malignancy in vitro and in vivo. CONCLUSION: Overall, we demonstrated that the anti-tumoral effects triggered by AT9283 treatment recapitulated the MKK3 depletion effects in all tested CRC models in vitro and in vivo, suggesting that AT9283 is a repurposed drug. According to its good tolerance when tested with primary colonocytes (CCD-18CO), AT9283 is a promising drug for the development of novel therapeutic strategies to target MKK3 oncogenic functions in late-stage and metastatic CRC patients.


Asunto(s)
Neoplasias Colorrectales , MAP Quinasa Quinasa 3 , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Animales , Ratones , MAP Quinasa Quinasa 3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Proliferación Celular/efectos de los fármacos , Autofagia/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
19.
Cell Rep Med ; 5(2): 101376, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38228147

RESUMEN

The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.


Asunto(s)
Neoplasias Colorrectales , Escherichia coli , Péptidos , Policétidos , Humanos , Irinotecán/farmacología , Escherichia coli/genética , Escherichia coli/metabolismo , Estudios Retrospectivos , ADN/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología
20.
Nat Commun ; 15(1): 7495, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39209908

RESUMEN

The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids. Multidimensional omics analyses indicate that tumoroids retain extensive molecular fidelity with parental PDXs. A tumoroid-based trial with the anti-EGFR antibody cetuximab reveals variable sensitivities that are consistent with clinical response biomarkers, mirror tumor growth changes in matched PDXs, and recapitulate EGFR genetic deletion outcomes. Inhibition of adaptive signals upregulated by EGFR blockade increases the magnitude of cetuximab response. These findings illustrate the potential of large living biobanks, providing avenues for molecularly informed preclinical research in oncology.


Asunto(s)
Cetuximab , Neoplasias Colorrectales , Receptores ErbB , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Cetuximab/uso terapéutico , Cetuximab/farmacología , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Ratones , Femenino , Metástasis de la Neoplasia , Masculino
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