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1.
Mol Oncol ; 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35060299

RESUMO

Although many studies highlight the implication of circular RNAs (circRNAs) in carcinogenesis and tumor progression, their potential as cancer biomarkers has not yet been fully explored in the clinic due to the limitations of current quantification methods. Here, we report the use of the nCounter platform as a valid technology for the analysis of circRNA expression patterns in non-small cell lung cancer (NSCLC) specimens. Under this context, our custom-made circRNA panel was able to detect circRNA expression both in NSCLC cells and formalin-fixed paraffin-embedded (FFPE) tissues. CircFUT8 was overexpressed in NSCLC, contrasting with circEPB41L2, circBNC2 and circSOX13 downregulation even at the early stages of the disease. Machine learning (ML) approaches from different paradigms allowed discrimination of NSCLC from non-tumor controls (NTCs) with an 8-circRNA signature. An additional 4-circRNA signature was able to classify early-stage NSCLC samples from NTC, reaching a maximum area under the ROC curve (AUC) of 0.981. Our results not only present two circRNA signatures with diagnosis potential, but also introduce nCounter processing following ML as a feasible protocol for the study and development of circRNA signatures for NSCLC.

2.
Thorac Cancer ; 12(23): 3141-3149, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34643053

RESUMO

INTRODUCTION: Tumor size is an absolute recurrence risk in lung cancer. Although morphological features also reflect recurrence risk, its significance among lower-risk cases characterized by small size is unknown. We aimed to evaluate the relationship between pathological invasive tumor size and morphological features, and their prognostic impact by considering them simultaneously in lung adenocarcinoma. PATIENTS AND METHODS: We retrospectively reviewed 563 pN0M0 patients with pathological invasive size of ≤40 mm. The patients were classified by pathological invasive size and pathological malignant grading using the proportion of subhistological components. The prognostic impact was evaluated using recurrence-free survival (RFS) and overall survival (OS). The impact on prognosis was evaluated using uni- and multivariate analyses. RESULTS: The proportion of histological grade changed according to invasive tumor size. Patients with high malignant grade (G3) showed worse RFS than those with low and intermediate malignant grade (G1+2) with invasive size ≤20 mm. The 5-year RFS (G1+2 vs. G3) in 5-10 mm was 96.0% vs. 83.3% (HR = 5.505, 95% CI = 7.156-1850, p < 0.001) and in 10-20 mm was 87.8% vs. 67.1% (HR = 2.829, 95% CI = 4.160-43.14, p < 0.001). G3 patients were significantly bigger in invasive size and included more pleural/lymphatic/vascular invasion and recurrence. Multivariate analysis indicated pathological G3 status was significantly associated with worse RFS (HR = 2.097, 95% CI = 1.320-3.333, p = 0.002). CONCLUSIONS: Invasive tumor size and pathological malignant grade overlap in invasive adenocarcinoma. G3 patients are more likely to have pleural/lymphatic/vascular invasion and significantly worse RFS compared to G1/G2 cases, even with a small invasive size of ≤20 mm.

3.
Br J Cancer ; 125(12): 1602-1611, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34373568

RESUMO

Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34218331

RESUMO

PURPOSE: Liquid biopsy for early-stage lung cancer diagnosis is challenging, and optimal candidates' clinicopathological features are unknown. We investigated utility and clinicopathological features of optimal candidates in somatic mutation-targeted liquid biopsy using droplet digital polymerase chain reaction (ddPCR) in pN0M0 EGFR mutation-positive lung adenocarcinoma patients. METHODS: We performed EGFR mutation-targeted ddPCR liquid biopsy in 100 patients with resected pN0M0 invasive lung adenocarcinoma, whose tumor diameter in high-resolution computed tomography (HRCT) was ≤ 5 cm. Peripheral blood-derived serum was collected preoperatively. Two representative EGFR somatic variants (exon 19 [E746-A750 del (2235_2249 del)]; exon 21 (L858R)) were utilized as liquid biopsy targets. Clinicopathological features including radiological appearance, subhistology, and invasive status were compared between ddPCR-positive and ddPCR-negative patients. RESULTS: Among the 100 patients, 98 showed part-solid or pure-solid appearance in HRCT and 2 showed non-solid appearance; 98 were pathological stage IA1-IB. Of the 66 patients with EGFR mutation detection in ddPCR, 12 were significantly positive and 10 (83.3%, 10/12) exhibited pure-solid appearance in HRCT. Clinical invasive tumor ratio was significantly higher in ddPCR-positive than in ddPCR-negative patients (median: 100% vs. 85.4%, P = 0.0212), whereas other clinicopathological features were not significantly different. CONCLUSION: Mutation-targeted liquid biopsy using ddPCR detected lung cancer in 12.0% (12/100) of pN0M0 EGFR-mutant lung adenocarcinoma patients. In 83.3% of the ddPCR-positive patients, tumors showed pure-solid appearance in HRCT. The detection ratio increased to 21.3% (10/47) among patients with pure-solid appearance tumors. Tumor appearance might be useful for better selection of liquid biopsy candidates.

5.
Clin Lung Cancer ; 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34321190

RESUMO

BACKGROUND: The aim of this study was to investigate and compare the clinical behaviors of combined and pure high-grade neuroendocrine carcinoma (large-cell neuroendocrine carcinoma [LCNEC] and small-cell lung carcinoma [SCLC]). PATIENTS AND METHODS: Data of 132 patients who underwent complete resection for combined or pure high-grade neuroendocrine carcinoma (combined group, 67; pure group, 65) between January 2001 and December 2015 were retrospectively reviewed. The clinicopathological features were analyzed and compared, and the prognoses were assessed by performing the Kaplan-Meier method and Cox regression analysis. RESULTS: The combined and pure groups had nearly equivalent clinicopathological characteristics, specifically, older males with smoking history, almost the same percentage of pleural/lymphatic/vascular invasion, and nearly the same recurrence rates and relapse patterns. The combined group had prognosis equivalent to that of the pure group (5-year overall survival [OS] rates: 61.8% vs. 52.2%, respectively; P = .82 and 5-year recurrence-free survival [RFS] rates: 42.4% vs. 43.9%, respectively; P = .96), and this trend was identified in sub-analyses only for patients with LCNEC, SCLC, and the same pathological stage. Multivariable Cox regression analysis in patients with high-grade neuroendocrine carcinoma revealed that vascular invasion and pathological stage were independent prognostic factors for OS; more importantly, combined and pure histologies were proven to have nearly equivalent associations with prognosis (hazard ratio, 0.96; 95% confidence interval, 0.22to 1.66; P = .96). RESULTS: Combined high-grade neuroendocrine carcinoma had clinical behavior equivalent to those of pure high-grade neuroendocrine carcinoma, with similar clinicopathological characteristics.

6.
J Clin Oncol ; 39(25): 2791-2802, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34077268

RESUMO

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Imunoterapia/mortalidade , Neoplasias Pulmonares/patologia , Neuregulina-1/genética , Proteínas de Fusão Oncogênica/genética , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologia
8.
Breast Cancer ; 28(5): 1062-1071, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34047951

RESUMO

BACKGROUND: Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. METHODS: In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K-AKT-mTOR signaling pathway was also examined. RESULTS: The relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. CONCLUSIONS: In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K-AKT-mTOR signaling pathway.

9.
J Cancer Res Clin Oncol ; 147(12): 3709-3718, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33796913

RESUMO

PURPOSE: The clinicopathological or genetic features related to the prognosis of mucinous adenocarcinoma are unknown because of its rarity. The clinicopathological or targetable features were investigated for better management of patients with mucinous adenocarcinoma of the lung. METHODS: We comprehensively evaluated the clinicopathological and genetic features of 60 completely resected mucinous lung adenocarcinomas. Targetable genetic variants were explored using nCounter and polymerase chain reaction, PD-L1 and TTF-1 expression were evaluated using immunohistochemistry. We analyzed the prognostic impact using the Kaplan-Meier method and log-rank test. RESULTS: Of the 60 enrolled patients, 13 (21.7%) had adenocarcinoma in situ/minimally invasive adenocarcinoma, and 47 (78.3%) had invasive mucinous adenocarcinoma (IMA). Fifteen patients (25%) showed a pneumonic appearance on computed tomography (CT). CD74-NRG1 fusion, EGFR mutations, and BRAF mutation were detected in three (5%), four (6.7%), and one (1.7%) patient(s), respectively. KRAS mutations were detected in 31 patients (51.7%). Two patients (3.5%) showed immunoreactivity for PD-L1. No in situ or minimally invasive cases recurred. IMA patients with pneumonic appearance had significantly worse recurrence-free survival (RFS) and overall survival (OS) (p < 0.001). Furthermore, IMA patients harboring KRAS mutations had worse RFS (p = 0.211). Multivariate analysis revealed that radiological pneumonic appearance was significantly associated with lower RFS (p < 0.003) and OS (p = 0.012). KRAS mutations served as an unfavorable status for RFS (p = 0.043). CONCLUSION: Mucinous adenocarcinoma had a low frequency of targetable genetic variants and PD-L1 immunoreactivity; however, KRAS mutations were frequent. Pneumonic appearance on CT imaging and KRAS mutations were clinicopathological features associated with a worse prognosis.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
11.
Lung Cancer ; 141: 107-113, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035371

RESUMO

OBJECTIVES: Recurrence risk of resected lung adenocarcinoma is represented by pathological stage (pStage), histological subtype, and potentially by EGFR mutation. However, the relationship among these factors and their combined impact on prognosis are unclear. MATERIALS AND METHODS: Using a multicenter database, we retrospectively investigated the prognostic impact of EGFR mutation status in relation to pStage and histological subtype in resected pN0-1M0 lung adenocarcinoma. RESULTS: Among 1155 pN0-1M0 adenocarcinoma cases, pStage 0 and IA1-IB were confirmed predominantly in EGFR-positive cases. AIS, MIA, and lepidic predominant adenocarcinoma were also more frequently found in EGFR-positive cases and showed no/little recurrence regardless of EGFR mutation status. The 5-year recurrence-free survival (RFS) of papillary, acinar, solid, and micropapillary predominant adenocarcinoma was stratified by pStage (IA1-IB, IIA-IIIA) or histological malignant subtype (intermediate or high malignant subtype), and more finely subdivided by EGFR mutation status. Positive EGFR mutation cases showed worse RFS in both classifications. Low malignant subtype and pStage IA1-IB intermediate malignant subtype showed low frequency of recurrence. Whereas, in pStage IA1-IB high malignant subtype and pStage IIA-IIIA cases, EGFR-positive cases showed poorer 5-year RFS than EGFR-negative (49.6% and 75.6%, respectively, hazard ratio [HR] = 1.84, 95% CI = 1.38-7.42, p <  0.01) and multivariate analysis indicated positive EGFR mutation status was significantly related to poorer PRF (HR = 2.005, 95% CI = 1.029-3.906, p =  0.041). CONCLUSION: EGFR mutation harbored primarily in early-stage or low-malignant histological subtypes with no/little recurrence. In pN0-1M0 adenocarcinoma with higher risk of recurrence, positive EGFR mutation cases showed worse RFS. EGFR mutation status enables better stratification of recurrence risk when considering pStage and histological malignant subtype.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/diagnóstico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Pneumonectomia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
12.
JTO Clin Res Rep ; 1(4): 100084, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34589963

RESUMO

Introduction: EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. Methods: We examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. Results: A total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05-3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. Conclusions: Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.

13.
Invest New Drugs ; 38(2): 485-492, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31428894

RESUMO

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.


Assuntos
Anorexia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Grelina/sangue , Neoplasias Pulmonares/tratamento farmacológico , Fitoterapia , Acilação , Adulto , Idoso , Anorexia/induzido quimicamente , Estudos Cross-Over , Ingestão de Energia/efeitos dos fármacos , Feminino , Humanos , Japão , Neoplasias Pulmonares/sangue , Masculino , Medicina Tradicional , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
14.
Ann Surg Oncol ; 27(3): 945-955, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31732945

RESUMO

BACKGROUND: Lung adenocarcinoma with the micropapillary (MP) component poses a higher risk of recurrence even when the MP component is not predominant. This study explored genetic features associated with highly malignant behavior of lung adenocarcinoma with the MP component. METHODS: The MP and papillary (PaP) components were captured separately in three patients. Comprehensive mRNA expressions of somatic variants were compared between the MP and PaP components of each patient using next-generation sequencing (NGS). The protein expression of the NGS-detected variant was validated by immunohistochemistry. The prognostic impact of the detected variant was evaluated in 288 adenocarcinoma patients with resection of pN0M0. RESULTS: In two cases, NGS suggested higher RNA expression of EGFR L858R in the MP component than in the PaP component (allele frequency, 0.485 vs. 0.155 and 1.000 vs. 0.526, respectively; P < 0.001 for both). Immunohistochemistry validated intense expression of L858R in the MP component of 27 MP-positive (MP+) patients. Among 288 pN0M0 patients, L858R was more frequently harbored in the MP+ patients than in the MP-negative (MP-) patients. The MP+ patients harboring L858R showed significantly worse recurrence-free survival (RFS) than the MP+ patients without L858R (median RFS 38.7 and 55.0 months, respectively; hazard ratio [HR] 3.004; 95% confidence interval [CI] 1.306-9.132; P = 0.012). Multivariate analysis of the MP+ patients showed that positive L858R status was associated with poorer RFS (HR 2.976; 95% CI 1.190-7.442; P = 0.020). CONCLUSIONS: EGFR L858R was more frequently harbored in the MP+ adenocarcinoma patients than in the MP- adenocarcinoma patients. Intense expression of L858R in the MP component was suggested, and the MP+ patients harboring L858R were at comparatively higher risk of recurrence in the group with pN0M0 lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/genética , Carcinoma Papilar/cirurgia , Receptores ErbB/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida
15.
Transl Lung Cancer Res ; 8(5): 667-673, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31737502

RESUMO

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. Methods: The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. Results: The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated. Conclusions: The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

16.
Cell Commun Signal ; 17(1): 137, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660987

RESUMO

INTRODUCTION: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. METHODS: The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. RESULTS: The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. CONCLUSIONS: Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.


Assuntos
Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Quinases Ativadas por p21/metabolismo , Células A549 , Adenocarcinoma/genética , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/antagonistas & inibidores
17.
Transl Lung Cancer Res ; 8(4): 340-351, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31555510

RESUMO

Background: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. Methods: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. Results: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. Conclusions: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.

18.
Expert Rev Respir Med ; 13(10): 1019-1028, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31411906

RESUMO

Introduction: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges. Areas covered: In this review we will focus on the mechanisms of resistance to the first-generation EGFR TKI, erlotinib, and will mainly summarize the findings throughout the last 10 years in the field of EGFR-mutant lung cancer. Expert opinion: Widespread research has been performed and several mechanisms of resistance to EGFR TKIs, especially first- and second-generation, have been identified. Still, no adequate combinatory therapies have received regulatory approval for the treatment of EGFR-mutant patients at the time of resistance. The third-generation EGFR TKI, osimertinib has been approved for patients whose tumor has become resistant through the secondary T790M resistant EGFR mutation. The identification of the mechanisms of resistance and the application of the adequate therapy to each patient is still an unmet need.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Reparo do DNA , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Mutação
19.
J Cancer Res Clin Oncol ; 145(9): 2325-2333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317326

RESUMO

PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated. METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence. RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy. CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmão/metabolismo , Linfonodos/metabolismo , Mutação , Transcriptoma/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
20.
Breast Cancer ; 26(5): 581-593, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30830684

RESUMO

PURPOSE: Pseudopodia are actin-rich ventral protrusions associated with cell motility and cancer cell invasion. We previously applied our established method of using excimer laser cell etching to isolate pseudopodial proteins from MDA-MB-231 breast cancer cells. We later identified 14-3-3γ as an oncogenic molecule among 46 candidate proteins that are specific to pseudopodia. The present study aimed to determine the function of 14-3-3γ in the motility of breast cancer cells. METHODS: MDA-MB-231 cells were cultured on 3-µm porous membranes and double stained to localize 14-3-3γ and phalloidin in pseudopodia using confocal imaging. We assessed pseudopodia numbers and length, as well as migration and wound healing in MDA-MB-231 cells with knockdown and forced expression of 14-3-3γ to determine 14-3-3γ involvement in cell motility. We also immunohistochemically analyzed 14-3-3γ in human breast cancer tissues with high-grade lymphatic invasion. RESULTS: We specifically located 14-3-3γ in pseudopodia of MDA-MB-231 cells. Knockdown and forced expression of 14-3-3γ, respectively, decreased and increased pseudopodial formation and elongation. Migration and wound healing assays also showed that 14-3-3γ knockdown and forced expression, respectively, decreased and increased the number of underside cells and acellular areas in MDA-MB-231 breast cancer cells. More 14-3-3γ was expressed in sites of lymphatic invasion, than in the center and periphery of human breast cancer tissues. CONCLUSION: The role of 14-3-3γ in breast cancer invasiveness might be to promote cell motility. Inhibition of 14-3-3γ could, therefore, become a novel target of therapy to prevent invasion and metastasis in patients with breast cancers expressing 14-3-3γ.


Assuntos
Proteínas 14-3-3/metabolismo , Neoplasias da Mama/patologia , Movimento Celular , Pseudópodes/metabolismo , Proteínas 14-3-3/genética , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Técnicas de Silenciamento de Genes , Humanos , Metástase Linfática/fisiopatologia , Células MCF-7 , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Células NIH 3T3 , Invasividade Neoplásica , Transfecção
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