Akira Mogi

TP53 Mutations in Nonsmall Cell Lung Cancer

The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non-Small-Cell Lung Cancer

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

Stimulation of tyrosine- and serine-phosphorylation of focal adhesion kinase in mouse 3T3 cells by fibronectin and fibroblast growth factor

Phosphorylation of both tyrosine and serine residues of focal adhesion kinase (FAK) was stimulated by the adhesion of BALB/c mouse 3T3 cells to fibronectin, but phosphorylation of threonine was not detectable. Acidic and basic fibroblast growth factors also stimulated the phosphorylation of serine and tyrosine of FAK in cells adhered to poly‐l‐lysine, but epidermal growth factor and platelet‐derived growth factor did not. A fusion protein of fibronectin and basic fibroblast growth factor effectively induced the phosphorylation of FAK. Phosphorylation of FAK in the rat myoblast L‐6 cell line, which lacks fibroblast growth factor receptors, was not stimulated by fibroblast growth factors, suggesting that the interaction of fibroblast growth factors with their receptors might cause the phosphorylation of FAK.

FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I–specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. Implications: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. Visual Overview: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg. Mol Cancer Res; 12(1); 32–37. ©2013 AACR.

Impact of preexisting pulmonary fibrosis detected on chest radiograph and CT on the development of gefitinib-related interstitial lung disease.

Objectives:Although preexisting pulmonary fibrosis (PF) on chest radiograph is known to be a risk factor of gefitinib-related interstitial lung disease (ILD), the significance of PF detected by chest computed tomography (CT) on the development of gefitinib-related ILD has not been investigated sufficiently. Methods:We reviewed 182 nonsmall cell lung cancer patients treated with gefitinib between July 2002 and March 2003. Chest radiographs and CT were taken in all patients periodically and reviewed by radiologists. PF was defined as ground-glass attenuation, consolidation, or reticular shadow without segmental distribution. Gefitinib-related ILD was defined as the acute respiratory failure developed during the course of gefitinib administration and lack of evidence for other cause of respiratory failure. Expected risk factors for gefitinib-related ILD were evaluated in multivariate analysis. Results:There were 15 patients with PF. Nine PF were detected on both chest radiograph and chest CT, and 6 on only chest CT. Twelve patients (6.6%) developed ILD during the course of gefitinib monotherapy and 4 died of it. Univariate and multivariate analyses showed that PF detected on chest radiograph was found to be the only significant risk factor for developing ILD (32.2, P < 0.001). Preexisting fibrosis diagnosed on chest CT but not apparent on chest radiograph was not significantly correlated with ILD. Conclusion:Gefitinib should not be given to patients with PF apparent on chest radiograph. Patients with PF on chest CT but not detected on chest radiograph could be treated carefully with gefitinib, but a risk-benefit analysis should be considered.

Lack of transforming growth factor‐β type II receptor expression in human retinoblastoma cells

Retinoblastoma cells are resistant to transforming growth factor‐β (TGF‐β) activity due to the absence of TGF‐β binding. To further elucidate the mechanism of TGF‐β resistance, we studied the expression of the TGF‐β receptors and SMADs by using the Y79 and WERI‐Rb‐1 retinoblastoma cell lines. Binding of 125I‐TGF‐β1 to serine/threonine kinase receptor type II (TβR‐II) and TβR‐I was not seen in the retinoblastoma cells. TβR‐II mRNA was not expressed in these cells, but TβR‐I mRNA was detected. Mutation analysis revealed no mutation in the coding region of the TβR‐II gene, and TβR‐II mRNA could be induced after the differentiation of Y79 cells. Smad2, Smad3, and Smad4, which are involved in TGF‐β signaling, were expressed in the retinoblastoma cells. Transcriptional activation of the TGF‐β‐responsive genes was not seen by the transfection of either recep‐tor cDNA alone but could be induced by transfection of both TβR‐II and TβR‐I. These data suggest that the defect in the TGF‐β response is caused by the lack of TβR‐II in the retinoblastoma cells. In addition, TβR‐I may be functionally inactivated in these cell lines. J. Cell. Physiol. 175:305–313, 1998.

Possible role of protein kinase C in the regulation of intracellular stability of focal adhesion kinase in mouse 3T3 cells.

Effects of various types of protein kinase inhibitor on the adhesion and spreading of BALB/c mouse 3T3 cells and on the phosphorylation and stability of focal adhesion kinase (FAK) in the cells were studied. Inhibitors of protein tyrosine kinases, methyl 2,5‐dihydroxycinnamate and herbimycin A, inhibited tyrosine‐phosphorylation of FAK and the adhesion of 3T3 cells to fibronectin. Among inhibitors of serine/threonine kinases tested, calphostin C, a specific inhibitor of protein kinase C, inhibited cell spreading rather than cell adhesion, and it induced the decrease of intracellular FAK within 30 min. Inhibitors of tyrosine kinase, A kinase, G kinase, and myosin light chain kinase did not induce such a rapid and specific decrease of FAK. When calphostin C (20 μM) was added to sub‐confluent monolayer cultures, serine‐phosphorylation of FAK was inhibited by 67% within 2 h, and decrease in the amount of FAK and rounding up of the cells began after 4 h. Label‐chase experiments indicated that about 60% of 35S‐labeled FAK degraded within 1–2 h after addition of calphostin C to monolayer cultures. These results indicated that serine‐phosphorylation of FAK induced by protein kinase C was important in the regulation of metabolic stability of FAK.

SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non‐small cell lung cancer

Despite advances in the development of various therapeutic agents, non‐small cell lung cancer (NSCLC) is associated with a poor prognosis. To improve the prognosis of patients with NSCLC, new therapeutic targets for overcoming drug resistance are required. The process of autophagy is required to support the tumorigenesis and drug resistance of cancer cells. We investigated the clinical significance of SIRT6, a member of the NAD+‐dependent deacetylase family, which regulates a variety of cancer‐related processes, including autophagy.

Pulmonary function after pulmonary resection by posterior thoracotomy, anterior thoracotomy or video-assisted surgery

OBJECTIVE Predicted postoperative forced expiratory volume in 1s (ppoFEV1) is estimated in lung cancer patients before pulmonary resection, as well as the clinical stage. This study aims to evaluate ppoFEV1 and ppo-vital capacity (ppoVC) on postoperative day 7 (POD7) and to compare the results following video-assisted thoracic surgery (VATS) and open thoracotomy procedures. METHODS Of the 155 patients who underwent pulmonary resection, 70 had VATS; 30 had muscle-sparing thoracotomy (anterior limiting thoracotomy (AL)); and 55 had postero-lateral thoracotomy (PL). VC and FEV1 were measured on POD7 and compared with the VC and FEV1 before surgery using analysis of covariance (ANCOVA). The ratio of the actual- and the ppoVC and FEV1 was evaluated to identify factors associated with variations in postoperative residual VC/FEV1. RESULTS There were significant differences by analysis of covariance (ANCOVA) in the VC/FEV1 among the three surgical approaches. In the VATS group, the VC ratio and the FEV1 ratio were 96.5% and 94.7%, respectively; they were significantly higher in the VATS group than in the thoracotomy group (AL: 90.4% and 90.1%, respectively; PL: 87.4% and 87.6%, respectively). Non-chronic obstructive pulmonary disease (COPD) and upper lobectomy were also associated with a low VC ratio and FEV1 ratio. CONCLUSION Predicted postoperative pulmonary function might be overestimated in COPD patients or in those undergoing VATS or lower lobectomy.

Primary mediastinal atypical meningioma: Report of a case and literature review

Meningiomas are common neoplasms arising from the central nervous system meninges. On the other hand, primary ectopic meningiomas are extremely rare and usually limited to the head and neck region or to the paravertebral soft tissues. Their occurrence in the mediastinum is even rarer. Until now, only 4 cases of primary mediastinal meningioma have been reported in the literature searched on Medline. Because of its rarity and intriguing pathogenesis, we report here a case of primary mediastinal meningioma that was treated by surgical resection. The clinical features, treatment, pathological findings, and prognosis are analyzed, and the literature on ectopic meningioma is reviewed.