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1.
Nature ; 595(7869): 730-734, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34290403

RESUMEN

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR)  by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Compuestos de Fenilurea/farmacología , Quinolinas/farmacología , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Gefitinib/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Receptores de Factores de Crecimiento de Fibroblastos , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Commun ; 15(1): 2581, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38519484

RESUMEN

Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics' specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Humanos , Femenino , Carcinoma Hepatocelular/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral/genética , Factor A de Crecimiento Endotelial Vascular , Células Mieloides/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Inmunosupresores , Inflamación/patología
3.
Mol Oncol ; 17(6): 964-980, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36650715

RESUMEN

Liver cancer is the fourth most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co-inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well-tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/genética , Proteínas Tirosina Quinasas Receptoras
4.
Nat Cancer ; 4(5): 665-681, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37081259

RESUMEN

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.


Asunto(s)
Glioblastoma , Ratones , Humanos , Animales , Glioblastoma/radioterapia , Linfocitos T Reguladores/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/uso terapéutico , Recurrencia Local de Neoplasia/metabolismo , Linfocitos T CD8-positivos , Inmunoterapia/métodos , Microambiente Tumoral
5.
Curr Protoc ; 1(6): e147, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34101385

RESUMEN

The rising incidence and increasing mortality of hepatocellular carcinoma (HCC), combined with its high tumor heterogeneity, lack of druggable targets, and tendency to develop resistance to chemotherapeutics, make the development of better models for this cancer an urgent challenge. To better mimic the high diversity within the HCC genetic landscape, versatile somatic murine models have recently been developed using the hydrodynamic tail vein injection (HDTVi) system. These represent novel in vivo tools to interrogate HCC phenotype and response to therapy, and importantly, allow further analyses of the associated tumor microenvironment (TME) shaped by distinct genetic backgrounds. Here, we describe several optimized protocols to generate, collect, and experimentally utilize various samples obtained from HCC somatic mouse models generated by HDTVi. More specifically, we focus on techniques relevant to ex vivo analyses of the complex liver TME using multiparameter flow cytometric analyses of over 21 markers, immunohistochemistry, immunofluorescence, and histochemistry. We describe the transcriptional assessment of whole tissue, or of isolated immune subsets by flow-cytometry-based cell sorting, and other protein-oriented analyses. Together, these streamlined protocols allow the optimal use of each HCC murine model of interest and will assist researchers in deciphering the relations between cancer cell genetics and systemic and local changes in immune cell landscapes in the context of HCC progression. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of HCC mouse models by hydrodynamic tail vein injection Basic Protocol 2: Assessment of HCC tumor progression by magnetic resonance imaging Basic Protocol 3: Mouse sacrifice and sample collection in HCC mouse models Support Protocol 1: Preparation of serum or plasma from blood Basic Protocol 4: Single-cell preparation and HCC immune landscape phenotyping by flow cytometry Alternate Protocol 1: Flow cytometric analysis of circulating immune cells Support Protocol 2: Generation, maintenance, and characterization of HCC cell lines Support Protocol 3: Fluorescence-activated cell sorting of liver single-cell preparation Basic Protocol 5: Preparation and immunohistochemical analysis of tumor tissues from HCC-bearing liver Alternate Protocol 2: Preparation and analyses for immunofluorescence staining of HCC-bearing liver Support Protocol 4: Liver-specific phenotypic analyses of liver sections Support Protocol 5: Immunohistochemical quantification in liver sections Basic Protocol 6: Preparation of snap-frozen tumor tissue from extracted liver and transcriptional analyses of bulk tumor or sorted cells Alternate Protocol 3: Protein analyses from HCC samples and serum or plasma.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/genética , Modelos Animales de Enfermedad , Neoplasias Hepáticas/genética , Ratones , Microambiente Tumoral
6.
Antibiotics (Basel) ; 3(1): 49-63, 2014 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-27025733

RESUMEN

Therapy failure of empirical antibiotic treatments prescribed by primary care physicians occurs commonly. The effect of such a treatment on the susceptibility to second line antimicrobial drugs is unknown. Resistance to amoxicillin was rapidly induced or selected in E. coli at concentrations expected in the patient's body. Strains with reduced susceptibility outcompeted the wild-type whenever antibiotics were present, even in low concentrations that did not affect the growth rates of both strains. Exposure of E. coli to amoxicillin caused moderate resistance to cefotaxime. The combined evidence suggests that initial treatment by amoxicillin has a negative effect on subsequent therapy with beta-lactam antibiotics.

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