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1.
Cancer Discov ; 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38241033

RESUMO

The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.

2.
Cancer Discov ; : OF1-OF22, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38270272

RESUMO

The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth. SIGNIFICANCE: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

3.
Tetrahedron Lett ; 54(45): 6008-6011, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25568501

RESUMO

A Julia-Kocienski approach to trifluoromethyl-substituted alkenes was evaluated in the reactions of 1,3-benzothiazol-2-yl, 1-phenyl-1H-tetrazol-5-yl, and 1-tbutyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfones with aldehydes. Among the various conditions tested, the best yields were obtained with 1-phenyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfone, in CsF-mediated, room temperature olefinations in DMSO. Aromatic aldehydes gave (trifluoromethyl)vinyl derivatives in 23-86% yields, with generally moderate stereoselectivity. Straightforward synthesis of the Julia-Kocienski reagent, and conversion to trifluoromethyl-substituted alkenes under mild reaction conditions, are the advantages of this approach.

4.
bioRxiv ; 2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-37131637

RESUMO

The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.

5.
Dis Model Mech ; 14(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34494649

RESUMO

Conditional ablation of defined cell populations in vivo can be achieved using genetically engineered mice in which the human diphtheria toxin (DT) receptor (DTR) is placed under control of a murine tissue-specific promotor, such that delivery of DT selectively ablates cells expressing this high-affinity human DTR; cells expressing only the endogenous low-affinity mouse DTR are assumed to be unaffected. Surprisingly, we found that systemic administration of DT induced rapid regression of murine lung adenocarcinomas that express human mutant EGFR in the absence of a transgenic allele containing human DTR. DT enzymatic activity was required for tumor regression, and mutant EGFR-expressing tumor cells were the primary target of DT toxicity. In FVB mice, EGFR-mutant tumors upregulated expression of HBEGF, which is the DTR in mice and humans. HBEGF blockade with the enzymatically inactive DT mutant CRM197 partially abrogated tumor regression induced by DT. These results suggest that elevated expression of murine HBEGF, i.e. the low-affinity DTR, confers sensitivity to DT in EGFR-mutant tumors, demonstrating a biological effect of DT in mice lacking transgenic DTR alleles and highlighting a unique vulnerability of EGFR-mutant lung cancers.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Animais , Toxina Diftérica/metabolismo , Toxina Diftérica/toxicidade , Receptores ErbB/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Neoplasias Pulmonares/genética , Camundongos , Receptores de Superfície Celular/metabolismo
6.
Cancer Discov ; 11(7): 1736-1753, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33707235

RESUMO

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.


Assuntos
Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos
7.
Cancer Res ; 80(10): 2017-2030, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32193290

RESUMO

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma/genética , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Adenocarcinoma/tratamento farmacológico , Afatinib/farmacologia , Alelos , Animais , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Pessoa de Meia-Idade , Mutação
8.
J Immunother Cancer ; 7(1): 172, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291990

RESUMO

BACKGROUND: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. METHODS: Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. RESULTS: We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs and increased maturation of alveolar macrophages. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. We also found that further efforts to boost the function and abundance of inflammatory cells, by combining erlotinib treatment with anti-PD-1 and/or a CD40 agonist, did not improve survival in an EGFR-driven mouse model. CONCLUSIONS: Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlight the importance of investigating targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/imunologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Camundongos Transgênicos , Mutação , Oncogenes , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
9.
Clin Cancer Res ; 22(2): 426-35, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26341921

RESUMO

PURPOSE: The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFR(T790M)). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR(T790M)-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy. EXPERIMENTAL DESIGN: Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFR(L858R)-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs. RESULTS: Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFR(T790M) mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR(T790M). CONCLUSIONS: These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted.


Assuntos
Adenocarcinoma/tratamento farmacológico , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Afatinib , Animais , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada/métodos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Mutação/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
10.
Cancer Cell ; 27(6): 751-3, 2015 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-26058074

RESUMO

The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors. In tyrosine kinase inhibitor-resistant lung tumors, rociletinib and AZD9291 are highly active when T790M is present and modestly active when T790M is absent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação
11.
Clin Cancer Res ; 21(17): 3818-20, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26169963

RESUMO

Third-generation mutant-specific EGFR tyrosine kinase inhibitors are showing robust clinical activity, particularly in lung cancers harboring the EGFR(T790M) mutation, yet acquired resistance to these agents emerges. Additional mutations in EGFR can confer resistance that, depending on their genomic context, could determine new drug sensitivities of the cancer cells.


Assuntos
Acrilamidas/farmacologia , Alelos , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Humanos
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