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1.
Cancer Cell ; 40(10): 1128-1144.e8, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36150391

RESUMO

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Decitabina , Genes ras , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
2.
Nat Cancer ; 3(4): 402-417, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35422503

RESUMO

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Trifosfato de Adenosina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia
3.
Sci Transl Med ; 13(609): eabb3738, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34516823

RESUMO

The clinical efficacy of epidermal growth factor receptor (EGFR)­targeted therapy in EGFR-mutant non­small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor­resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.


Assuntos
Receptores ErbB , Neoplasias Pulmonares , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
4.
Mol Cancer Ther ; 20(4): 641-654, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33536188

RESUMO

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.


Assuntos
Genes ras/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Oncogenes/genética , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia
5.
Mol Oncol ; 15(1): 27-42, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191822

RESUMO

Small-cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next-generation sequencing (NGS) and by characterizing a representative patient-derived model. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. We established a patient-derived model from one such patient (DFCI168) harboring an NRASQ61K mutation and characterized the sensitivity of this model to MEK and TORC1/2 inhibitors. Despite the clinical diagnosis of SCLC, the majority (8/11) of cases were either of nonpulmonary origin or of mixed histology and included atypical carcinoid (n = 1), mixed non-small-cell lung carcinoma and SCLC (n = 4), unspecified poorly differentiated carcinoma (n = 1), or small-cell carcinoma from different origins (n = 2). RB1 and TP53 mutations were found in four and five cases, respectively. Predicted driver mutations were detected in EGFR (n = 2), NRAS (n = 1), KRAS (n = 1), BRCA1 (n = 1), and ATM (n = 1), and one case harbored a TMPRSS2-ERG fusion. DFCI168 (NRASQ61K ) exhibited marked sensitivity to MEK inhibitors in vitro and in vivo. The combination of MEK and mTORC1/2 inhibitors synergized to prevent compensatory mTOR activation, resulting in prolonged growth inhibition in this model and in three other NRAS mutant lung cancer cell lines. SCLC in never/former light smokers is rare and is potentially a distinct disease entity comprised of oncogenic driver mutation-harboring carcinomas morphologically and/or clinically mimicking SCLC. Comprehensive pathologic review integrated with genomic profiling is critical in refining the diagnosis and in identifying potential therapeutic options.


Assuntos
Heterogeneidade Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Fumantes , Idoso , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Mutação/genética , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/patologia , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
6.
IDCases ; 17: e00578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309037

RESUMO

Helicobacter cinaedi is a rarely encountered pathogen that easily induces bacteremia. Various foci of H. cinaedi infection have been reported; however, no case of adnexal abscess caused by H. cinaedi has been reported in the English literature. We herein report a case of ovarian abscess caused by H. cinaedi. A 38-year-old nulligravid Japanese woman was admitted to our hospital with an adnexal abscess. Clinical findings included fever, leukocytosis, and elevated C-reactive protein. Laparoscopic right partial oophorectomy with abdominal lavage was performed. H. cinaedi was isolated from cultures of blood and ovarian abscess fluid after surgery. Intravenous ampicillin/sulbactam was administered for 2 weeks, followed by oral amoxicillin for an additional 2 weeks. The postoperative course was uneventful and clinical findings improved. There was no evidence of relapse. H. cinaedi can cause ovarian abscess and is likely an under-recognized pathogen.

7.
Cancer Res ; 77(10): 2712-2721, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28363995

RESUMO

Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712-21. ©2017 AACR.


Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Éxons , Mutagênese Insercional , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Adulto , Substituição de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Códon , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/química , Feminino , Expressão Gênica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/química , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Discov ; 5(9): 960-971, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26036643

RESUMO

UNLABELLED: Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer. SIGNIFICANCE: Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Cancer Res ; 19(16): 4532-40, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23833300

RESUMO

PURPOSE: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. EXPERIMENTAL DESIGN: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. RESULTS: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wild-type patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. CONCLUSIONS: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Códon , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Resultado do Tratamento
10.
Lung Cancer ; 75(2): 161-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21767894

RESUMO

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC(50) values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16 µM while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4 µM. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGFR-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Cloridrato de Erlotinib , Gefitinibe , Humanos , Camundongos , Mutação , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Res ; 71(18): 6051-60, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21791641

RESUMO

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Crizotinibe , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Modelos Moleculares , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais
12.
Gan To Kagaku Ryoho ; 37(3): 439-42, 2010 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-20332679

RESUMO

Adjuvant chemotherapy after complete resection in Stage I B-III A non-small cell lung cancer is recommended. Several clinical trials of adjuvant chemotherapy are now underway in Japan. Our institute also participates in adjuvant clinical trials, but slow patient recruitment is a problem. In this paper, we reported the current status of adjuvant chemotherapy and recruitment for clinical trials at our institute. Between August 2001 and December 2008, candidates for adjuvant chemotherapy were 315 patients. Among them 186 who received adjuvant chemotherapy were younger and had less co-morbidity than those who did not receive adjuvant chemotherapy. Twenty-five of the 186 patients participated in the clinical trials. The major reason of refusal of a clinical trial was that patients preferred to choose their own treatment and disliked randomized trials.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias Pulmonares/tratamento farmacológico , Seleção de Pacientes , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Japão , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/cirurgia , Tegafur/uso terapêutico , Uracila/uso terapêutico , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , Gencitabina
13.
Cancer Res ; 69(12): 5091-8, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19491268

RESUMO

Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal growth factor receptor (EGFR) and rearranged during transfection receptor signaling, which has shown promising results in clinical trials for advanced non-small cell lung cancer. However, the mechanisms of acquired resistance to vandetanib remain unclear. Therefore, we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro. Compared with PC-9 cells, PC-9/VanR cells showed emergence of an EGFR T790M mutation, moderately elevated MET amplification, and similar VEGFR-2 inhibition by vandetanib. Note that phospho-MET in PC-9/VanR was suppressed following EGFR inhibition by an irreversible EGFR-TKI, indicating that MET signaling of PC-9/VanR was dependent on EGFR signaling and that MET amplification was not the primary mechanism of resistance to vandetanib. In contrast to the in vitro experiment, vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of VEGFR-2 inhibition. In conclusion, the multitarget TKI vandetanib induced or selected for the EGFR T790M mutation as observed previously with highly selective EGFR-TKIs. However, vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs.


Assuntos
Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Receptores ErbB/genética , Neoplasias Pulmonares/patologia , Mutação , Piperidinas/farmacologia , Quinazolinas/farmacologia , Adenocarcinoma/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Fosforilação , Reação em Cadeia da Polimerase , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
14.
J Cancer Res Clin Oncol ; 135(8): 1055-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19152002

RESUMO

PURPOSE: The purpose of this study was to prospectively assess the clinical implications of neuroendocrine (NE) differentiation in non-small-cell lung cancer (NSCLC) tumors. METHODS: This study accrued subjects suspected to have lung cancer who underwent diagnostic bronchoscopy. Bronchoscopically-biopsied specimens were subjected to routine pathologic examination, and immunohistochemical studies were then performed if lung cancer was diagnosed. Chromogranin-A, synaptophysin, neural cell adhesion molecule, and Leu7 were used to demonstrate NE differentiation. RESULTS: A total of 280 subjects were accrued to this study over a period of 2 years. Among them, 149 subjects were assessable for this study, and 130 were diagnosed as having NSCLC tumors (55 adenocarcinomas, 50 squamous cell carcinomas, 24 NSCLCs not otherwise specified, and 1 typical carcinoid). Large cell NE carcinoma was not observed in this study. Immunohistochemically, NE differentiation was detected in 16% of NSCLC tumors excluding typical carcinoid. By status of NE differentiation of NSCLC tumors, progression-free survivals were similar in 73 patients undergoing non-surgical treatment (positive, n = 10; negative, n = 63) and 43 patients undergoing surgical resection (positive, n = 8; negative, n = 35), respectively. Overall survival of patients with NE-positive tumors appeared to be favorable both for those undergoing non-surgical treatment and those undergoing surgical resection, though the differences in survival were not significant (P = 0.11 and 0.35, respectively). CONCLUSIONS: NE differentiation was detected in 16% of NSCLC tumors in our study. However, the prognostic implications of the presence of this feature could not be clearly determined in this study.


Assuntos
Carcinoma Neuroendócrino/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Células Neuroendócrinas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Diferenciação Celular , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Células Neuroendócrinas/química , Estudos Prospectivos
15.
Gan To Kagaku Ryoho ; 35(6): 896-9, 2008 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-18633216

RESUMO

The efficacy of anti neoplastic agents for chest catheter pleurodesis remains controversial, and little is known regarding the optimal treatment protocol. Of the various anti neoplastic agents, bleomycin and cisplatin are preferred for intrapleural therapy in Japan, and a wide variation among institutions is evident in agent doses and medication methods for pleurodesis. In many reported trials of anti neoplastic pleurodesis, problems exist such as disease heterogeneity, small sample size and differences in response criteria, and randomized control trials (RCTs) are needed to establish evidence. The JCOG 9515 trial randomly assigned patients to either the bleomycin (BLM) arm, the OK-432 arm, or the cisplatin+etoposide (PE) arm. Among them, OK-432 was demonstrated to be more effective than BLM or PE in terms of pleural progression-free survival. Intrapleural combination therapy (chemotherapy plus biological response modifiers) appeared to be superior to either alone, and further randomized studies are warranted.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias Pleurais/tratamento farmacológico , Antineoplásicos/efeitos adversos , Humanos , Infusões Parenterais , Japão , Neoplasias Pleurais/complicações , Neoplasias Pleurais/patologia , Pleurisia/tratamento farmacológico , Pleurisia/etiologia , Aderências Teciduais
16.
Cancer Res ; 67(16): 7807-14, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17699786

RESUMO

The epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration of gefitinib may eventually induce acquired resistance in such patients. To gain insight into the mechanisms of this phenomenon, we placed PC-9, a cell line derived from pulmonary adenocarcinoma that has a 15-bp deletion in EGFR exon 19, under the continuous selective pressure of low levels of gefitinib without any mutagen, and established a subline that was able to grow in the presence of 2 micromol/L of gefitinib (designated RPC-9). In this cell line, about half of the reverse transcription-PCR products from mutated EGFR also carried an additional mutation (T790M). In keeping with the proposed role of T790M in abrogating gefitinib binding with EGFR, gefitinib-treated RPC-9 hardly displayed any decrease in the constitutive phosphorylation of EGFR, Akt, or Erk1/2 unlike in PC-9 cells. Interestingly, transfection of the EGFR carrying only a 15-bp deletion reversed the resistance to gefitinib in RPC-9 cells. Thus, the balance of expression levels between gefitinib-sensitive or gefitinib-resistant EGFR may govern the response to gefitinib in lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Quinazolinas/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-3/biossíntese
17.
J Thorac Oncol ; 2(4): 321-4, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17409805

RESUMO

We previously reported one patient with squamous cell carcinoma of the lung that showed the long-term effect to gefitinib with complete response. In the present report, we examine the epidermal growth factor receptor (EGFR) and K-RAS, HER2, and B-RAF mutations in this patient to find a B-RAF exon11 mutation, resulting in a substitution of valine by phenylalanine at codon 470 (V470F) as a novel type of B-RAF mutation in human cancers. In addition, the fluorescence in situ hybridization analysis for EGFR showed the high polysomy status. B-RAF is a nonreceptor serine/threonine kinase whose kinase domain has a structure similar to other protein kinases, including EGFR members. Of interest, the B-RAF V470F mutation corresponds to a position similar to the EGFR G719X mutation located on the phosphate binding (P)-loop of EGFR that clamps ATP into the catalytic cleft. This observation suggests that gefitinib may have an anti-cancer effect on B-RAF mutant tumors. Indeed, previous reports demonstrated that H1666 cells harboring B-RAF G465V mutations showed sensitivity to gefitinib, inhibiting phosphorylation of ERK1/2. We examined the effect of gefitinib on transient transfectants of the B-RAF mutant, but no drastic inhibition of ERK1/2 phosphorylation that was one of the downstream molecules of B-RAF was induced by gefitinib. In summary, we found a novel B-RAF V470F mutation in lung squamous cell carcinoma that showed response to gefitinib. However, our in vitro investigation did not explain the response observed in this particular patient. Further investigation is necessary to elucidate the mechanism of tumor sensitivity to EGFR tyrosine kinase inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Quinazolinas/farmacologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Análise Mutacional de DNA , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Genes ras/efeitos dos fármacos , Genes ras/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/efeitos dos fármacos , Quinazolinas/uso terapêutico , Receptor ErbB-2/efeitos dos fármacos , Receptor ErbB-2/genética , Sensibilidade e Especificidade , Transfecção , Células Tumorais Cultivadas/efeitos dos fármacos
18.
Cancer Sci ; 98(3): 357-63, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17270025

RESUMO

Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/genética , Mutação , Quinazolinas/metabolismo , Transdução de Sinais , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Gefitinibe , Genes ras , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transfecção
19.
Am J Hematol ; 81(5): 349-54, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16628731

RESUMO

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Leucemia Promielocítica Aguda , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/complicações , Análise por Conglomerados , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Humanos , Incidência , Leucemia Promielocítica Aguda/induzido quimicamente , Leucemia Promielocítica Aguda/epidemiologia , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico
20.
Acta Oncol ; 44(7): 717-22, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16227162

RESUMO

We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). We retrospectively compared toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with the same outcomes in patients aged younger than 75 years. In total, 350 patients were eligible for this analysis, of whom 92 were in the elderly group and 258 in the non-elderly group. In the elderly group, adverse events were generally mild to moderate and grade 3-4 adverse events were observed in 8 (9%) patients. The objective response rate (17 vs. 21% for elderly vs. non-elderly, respectively) and median survival time (7.6 vs. 9.3 months) were also similar in the two groups. Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91-22.72, p = 0.0642). In this study, treatment with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/secundário , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Segurança , Taxa de Sobrevida , Resultado do Tratamento
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