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Publications (61)

  • Article · May 2016 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: Programmed cell death 1 (PD-1) negatively regulates antigen receptor signaling upon binding by either of its ligands, programmed cell death ligand 1 or 2 (PD-L1/2). Blockade of this interaction with either PD-1 or PD-L1 antibodies has been successful in the treatment of human cancer, especially melanoma and non-small cell lung cancer. PD-L1 expression has been proposed as a predictor of tumor response. However, the relationships between PD-L1 expression and various clinicopathological characteristics remain unclear.
    Article · May 2016
  • Kenichi Suda · Isao Murakami · Hui Yu · [...] · Fred R. Hirsch
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Epidermal growth factor receptor (EGFR) gene somatic mutation is reportedly homogeneous. However there is little data regarding the heterogeneity of mutant-EGFR protein expression and EGFR gene copy number, especially in extra-thoracic lesions. These types of data may enhance our understandings of the EGFR-mutated lung cancer biology and our understanding of the heterogeneous response patterns to EGFR-TKIs. Methods: An 81-year old never-smoking female with lung adenocarcinoma could not receive any systemic therapy due to her poor performance status. After her death, fifteen tumor specimens from different sites were obtained by autopsy. Mutant-EGFR protein expression and EGFR gene copy numbers were assessed by immunohistochemistry (IHC) and by silver in situ hybridization (SISH), respectively. Heterogeneity in these EGFR aberrations was compared between metastatic sites (distant vs. lymph node) or histological morphologies (micropapillary vs. non-micropapillary). Results: All lesions showed positive staining for mutant-EGFR protein, except for 40% of the papillary component in one of pulmonary metastases (weak staining below 1+ threshold). Mutant-specific EGFR protein expression, evaluated by H-score, was significantly higher in micropapillary components compared with non-micropapillary components (Mann-Whitney U test, p = 0.014). EGFR gene copy number was quite different between lesions, but not correlated with histological morphology or metastatic form. However, EGFR gene copy numbers were similar between histological morphologies in each lesion. Conclusion: These data indicate that EGFR-mutant protein expression and EGFR gene copy number do not change as a consequence of tumor progression. This also justifies the biopsies from metastases as a surrogate for primary tumors.
    Article · May 2016 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
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    Katsuaki Sato · Kenichi Suda · Shigeki Shimizu · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations.
    Full-text Article · Apr 2016 · PLoS ONE
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    Hiroshi Mizuuchi · Kenichi Suda · Isao Murakami · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Table S1. Primer set for PCR.
    Full-text Dataset · Apr 2016
  • Hiroshi Mizuuchi · Kenichi Suda · Isao Murakami · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKIs. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose to describe this phenomenon as "oncogene swap". Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKIs. This possibility should be considered in order to avoid futile inhibition of the original oncogene. This article is protected by copyright. All rights reserved.
    Article · Feb 2016 · Cancer Science
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected NSCLC samples were target-resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in 9 samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in 3 samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of 4 mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusion: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth inhibitory effect of collagen.
    Article · Jan 2016 · Clinical Cancer Research
  • Masaya Nishino · Kenichi Suda · Takuya Iwasaki · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: A 55-year-old woman, who had been treated for nephrotic syndrome, was referred to our department due to an asymptomatic nodule at the anterior mediastinum. She had a past history of intestinal tuberculosis. The anterior mediastinal nodule was 2 cm in diameter, adhering to the left upper lobe of the lung, as revealed by computed tomography. FDG-PET scan showed a strong accumulation of FDG in the mediastinal nodule (SUVmax: 6.93), and weak accumulation of FDG was also noted in the supraclavicular, mediastinal, and hilar lymph nodes. As a diagnostic and therapeutic procedure, surgical resection using video-assisted thoracic surgery (VATS) was performed, with combined resection of the left upper lobe of the lung. The tumor was filled with pus that was positive for Mycobacterium tuberculosis on by PCR examination. Pathological examination identified epithelioid granuloma with caseous necrosis in the thymic tissue. Although thymic tuberculosis is a rare disease, the possibility of it should be kept in mind when treating a patient with an anterior mediastinal nodule irrespective of the past history of tuberculosis.
    Article · Jan 2016 · The Journal of the Japanese Associtation for Chest Surgery
  • Article · Nov 2015 · Annals of Oncology
  • Kenichi Suda · Isao Murakami · Kazuko Sakai · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients.
    Article · Nov 2015
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    Kenichi Suda · Isao Murakami · Kazuko Sakai · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.
    Full-text Article · Sep 2015 · Scientific Reports
  • [Show abstract] [Hide abstract] ABSTRACT: Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL. This article is protected by copyright. All rights reserved.
    Article · Sep 2015 · International Journal of Cancer
  • Article · Sep 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Mutational status of lung cancers between 2001-2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally-introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first generation (1G)- (gefitinib and erlotinib), 2G- (afatinib, dacomitinib, and neratinib), and 3G-TKIs (AZD9291 and CO1686) were determined. Among 1355 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations including G719X, E709X, and Del18 were present in 3.2%. Transfected Ba/F3 cells grew in the absence of interleukin-3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G- and 3G-TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11~50-fold), whereas IC90s of afatinib were only 3~7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5~25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (~80%) than to 1G-TKIs (35-56%) by compilation of data in the literatures. Lung cancers harboring exon 18 mutations shouldn't be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits can't detect all exon 18 mutations. Copyright © 2015, American Association for Cancer Research.
    Article · Jul 2015 · Clinical Cancer Research
  • Kenichi Suda · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Lung cancers with an epidermal growth factor receptor (EGFR) gene mutation account for ~40 % of adenocarcinomas in East Asians and ~15 % of those in Caucasians and African Americans, which makes them one of the most common molecularly defined lung cancer subsets. The discriminative clinical and pathological features of lung cancers with EGFR mutations have been intensively studied, and the predictive role of an EGFR mutation for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) is well established. However, controversial issues remain regarding the clinical and therapeutic implications of EGFR mutations in lung cancers. These include the prognostic impact of the EGFR mutation, its predictive implication for successful treatment with anticancer agents other than EGFR-TKIs, appropriate cytotoxic agents for lung cancers with this mutation, and the chemosensitivity of EGFR-mutation-positive lung cancers after acquisition of resistance to EGFR-TKIs. In this review, we discuss these unanswered but important questions, referring to in vitro studies, basic research, retrospective analyses, and the results of phase III clinical trials.
    Article · May 2015 · Archives of Toxicology
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    Hiroshi Mizuuchi · Kenichi Suda · Katsuaki Sato · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.
    Full-text Article · Apr 2015 · PLoS ONE
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    Kenji Tomizawa · Kenichi Suda · Toshiki Takemoto · [...] · Yukinori Sakao
    [Show abstract] [Hide abstract] ABSTRACT: Background Although lobe-specific nodal spread of primary lung cancer has been recently described, segment-specific nodal spread remains unclear. We investigated the frequency of hailer and mediastinal lymph node involvement and survival in patients with tumors located in the superior segment (SS) and basal segment (BS) in the right lower lobe.Methods Two hundred and sixty-three patients with primary lung cancer originating in the right lower lobe underwent lobectomy with systematic mediastinal lymph node dissection. Patients were categorized into two groups: SS (n = 114) or BS (n = 149).ResultsFrequencies of metastasis to station 11s and 11i were significantly higher in the SS (P < 0.0001) and BS groups (P = 0.022), respectively. Both the SS and BS groups showed a high frequency of subcarinal mediastinal zone (station 7) metastasis (96.9% and 90.6%, respectively; P = 0.271). The frequencies of superior mediastinal zone (station 2R and 4R) metastasis were 37.5% in the SS and 35.8% in the BS group (P = 0.878). In patients with pN2 disease, three-year disease-free survival was significantly shorter in the SS (22.6%) than the BS group (42.1%; P = 0.020). In the BS group, the independent predictive factors of a poor or good prognosis were metastasis to station 11i or skip metastasis, respectively; however, we did not detect an independent prognostic factor in the SS group. In the right lower lung lobe, there was no segment-specific nodal spread.Conclusion When segmentectomy is undertaken, mediastinal lymph node dissection should be performed in proportion to lobectomy.
    Full-text Article · Mar 2015 · Thoracic Cancer
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    Kenji Tomizawa · Kenichi Suda · Toshiki Takemoto · [...] · Tetsuya Mitsudomi
    [Show abstract] [Hide abstract] ABSTRACT: We present the first reported case of lung large cell neuroendocrine carcinoma (LCNEC) with spontaneous regression followed by progression. An 85-year-old woman presented with a 2.8-cm nodule in the right upper lung lobe on chest computed tomography. After four months, the tumor decreased to 1.8 cm and remained unchanged in size for the next three months, but it grew to 8.6 cm and invaded the mediastinal fat tissue after approximately one year. Ultrasound echo-guided percutaneous biopsy revealed the tumor to be LCNEC. The patient underwent a right upper lobectomy with lymph node dissection. She had a good postoperative course with no complications. Physicians and surgeons should be aware that radiographic regression of a pulmonary nodule does not necessarily exclude the possibility of lung cancer.
    Full-text Article · Feb 2015 · Thoracic Cancer
  • Kenichi Suda · Tetsuya Mitsudomi
    Article · Feb 2015 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
  • [Show abstract] [Hide abstract] ABSTRACT: A 71-year-old woman presented with an abnormal chest shadow on routine chest radiograph. Contrast enhanced chest computed tomography (CT) showed a heterogeneous mass in the anterior mediastinum with invasion to the right lung, pericardium, and superior vena cava (SVC). Positron emission tomography-CT showed high FDG accumulation (SUVmax: 13.51). Under a diagnosis of invasive thymoma or thymic carcinoma, the patient underwent tumor resection with combined resection of the right upper lobe of the lung, pericardium, phrenic nerve, and SVC. The tumor was white and solid at the cut surface. Histopathologically, the tumor was diagnosed as large-cell neuroendocrine carcinoma of the thymus. Twelve months later, mediastinal lymph node and multiple liver metastases developed. The patient was treated with combination chemotherapy consisting of carboplatin and etoposide for 4 cycles, leading to a partial response. However, multiple bone metastases were newly diagnosed.
    Article · Jan 2015 · The Journal of the Japanese Associtation for Chest Surgery