Details of a Researcher - Yasuda, Hiroyuki

Papers - Yasuda, Hiroyuki

Division display 21 - 40 of about 111 ／ All the affair displays >>

Real-world clinical practice for advanced non-small-cell lung cancer in the very elderly: A retrospective multicenter analysis.

Takahiro Fukushima, Yoshitaka Oyamada, Shinnosuke Ikemura, Shigenari Nukaga, Takashi Inoue, Daisuke Arai, Keiko Ohgino, Aoi Kuroda, Kota Ishioka, Fumio Sakamaki, Yusuke Suzuki, Hideki Terai, Hiroyuki Yasuda, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima

Clinical lung cancer 23 ( 6 ) 532 - 541 2022.09

ISSN 15257304

BACKGROUND: The optimal treatment for advanced non-small cell lung cancer (NSCLC) in very elderly patients is unclear. We aimed to evaluate their treatment in real-world clinical practice and identify suitable therapy that can improve their prognosis. MATERIALS AND METHODS: The medical records of 132 Japanese patients aged 80 years and older with advanced NSCLCs who were enrolled at a university hospital and its 9 affiliates were retrospectively analyzed. Clinical characteristics and overall survival (OS) were compared based on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and biomarker statuses. Patients were defined as biomarker-positive if programmed death-ligand 1 tumor proportion score (PD-L1 TPS) was ≥ 50% or activating mutations were present in epidermal growth factor receptor, anaplastic lymphoma kinase, or c-ros oncogene 1. Finally, the factors contributing to better prognosis were explored in both PS 0 - 2 and PS 3 - 4 patient groups. RESULTS: The PS 0 - 2 patients showed a longer median OS than the PS 3 - 4 patients (5.5 vs. 1.6 months). PS 0 - 2 patients with positive biomarkers who received chemotherapy showed a significantly longer median OS than those without (18.1 vs. 3.7 months). Among the biomarker-negative/unknown PS 0 - 2 patients, the median OS showed no significant difference between those who received chemotherapy and those who did not (4.5 vs. 3.1 months). The multivariate analysis showed that treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors was related to better prognoses in the PS 0 - 2 group. CONCLUSION: Biomarker-matched therapy is effective even in very elderly patients. Meanwhile, the effectiveness of chemotherapy for biomarker-negative/unknown PS 0 - 2 patients is questionable.

Access to Document (DOI)

A 70-Year-Old Woman With Long-Term Nonresolving Pneumonia.

Tomiyasu S, Kabata H, Emoto K, Azekawa S, Maeda C, Masai K, Yasuda H, Fukunaga K

Chest 161 ( 4 ) e219 - e223 2022.04

ISSN 0012-3692

Access to Document (DOI)

Long-Term Treatment-Free Survival After Multimodal Therapy in a Patient with Stage IV Lung Adenocarcinoma.

Hatsuyo Takaoka, Hideki Terai, Katsura Emoto, Lisa Shigematsu, Fumimaro Ito, Ayaka Saito, Masahiko Okada, Keiko Ohgino, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Nakachi, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima

OncoTargets and therapy 15 981 - 989 2022

ISSN 1178-6930

We report the first case of a patient with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) who achieved disease- and treatment-free survival for nearly 10 years. A 50-year-old man was diagnosed with NSCLC with MPE and underwent chemotherapy and salvage thoracic surgery. The patient received chemotherapy with cisplatin, pemetrexed, and bevacizumab, and a partial response was achieved. After informed consent was obtained from the patient, right middle lobectomy was performed to achieve local tumor control. Postoperative adjuvant chemotherapy with pemetrexed and bevacizumab was discontinued after almost 1 year of chemotherapy due to side effects such as diarrhea and muscle weakness. The patient has survived without recurrence of lung cancer for more than 11 years after being diagnosed and nearly 10 years after discontinuing chemotherapy.

Access to Document (DOI)

A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer

Yasuda H., Ichihara E., Sakakibara-Konishi J., Zenke Y., Takeuchi S., Morise M., Hotta K., Sato M., Matsumoto S., Tanimoto A., Matsuzawa R., Kiura K., Takashima Y., Yano S., Koyama J., Fukushima T., Hamamoto J., Terai H., Ikemura S., Takemura R., Goto K., Soejima K.

Lung Cancer (Lung Cancer) 162 140 - 146 2021.12

ISSN 01695002

Objectives: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Materials and methods: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. Results: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Conclusions: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

Access to Document (DOI)

Longitudinal Assessment of Prognostic Understanding in Patients with Advanced Lung Cancer and Its Association with Their Psychological Distress

Arai D., Sato T., Nakachi I., Fujisawa D., Takeuchi M., Sato Y., Kawada I., Yasuda H., Ikemura S., Terai H., Nukaga S., Inoue T., Nakamura M., Oyamada Y., Terashima T., Sayama K., Saito F., Sakamaki F., Naoki K., Fukunaga K., Soejima K.

Oncologist (Oncologist) 26 ( 12 ) e2265 - e2273 2021.12

ISSN 10837159

Background: Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time. Materials and Methods: We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being. Results: The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p =.010 and p =.014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer–specific symptom burden at 3 months (p =.008 and p =.005, respectively) and lower emotional well-being at 6 months (p =.006). Conclusion: Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately. Implications for Practice: This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.

Access to Document (DOI)

Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

Nakagawara K, Namkoong H, Terai H, Masaki K, Tanosaki T, Shimamoto K, Lee H, Tanaka H, Okamori S, Kabata H, Chubachi S, Ikemura S, Kamata H, Yasuda H, Kawada I, Ishii M, Ishibashi Y, Harada S, Fujita T, Ito D, Bun S, Tabuchi H, Kanzaki S, Shimizu E, Fukuda K, Yamagami J, Kobayashi K, Hirano T, Inoue T, Kagyo J, Shiomi T, Ohgino K, Sayama K, Otsuka K, Miyao N, Odani T, Oyamada Y, Masuzawa K, Nakayama S, Suzuki Y, Baba R, Nakachi I, Kuwahara N, Ishiguro T, Mashimo S, Minematsu N, Ueda S, Manabe T, Funatsu Y, Koh H, Yoshiyama T, Saito F, Ishioka K, Takahashi S, Nakamura M, Goto A, Harada N, Kusaka Y, Nakano Y, Nishio K, Tateno H, Edahiro R, Takeda Y, Kumanogoh A, Kodama N, Okamoto M, Umeda A, Hagimura K, Sato T, Miyazaki N, Takemura R, Sato Y, Takebayashi T, Nakahara J, Mimura M, Ogawa K, Shimmura S, Negishi K, Tsubota K, Amagai M, Goto R, Ibuka Y, Hasegawa N, Kitagawa Y, Kanai T, Fukunaga K

BMJ open respiratory research 8 ( 1 ) 2021.11

Access to Document (DOI)

Nasal delivery of single-domain antibody improves symptoms of SARS-CoV-2 infection in an animal model

Haga K., Takai-Todaka R., Matsumura Y., Song C., Takano T., Tojo T., Nagami A., Ishida Y., Masaki H., Tsuchiya M., Ebisudani T., Sugimoto S., Sato T., Yasuda H., Fukunaga K., Sawada A., Nemoto N., Murata K., Morimoto T., Katayama K.

PLoS Pathogens (PLoS Pathogens) 17 ( 10 ) e1009542 2021.10

ISSN 15537366

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.

Access to Document (DOI)

Upregulation of FGF9 in lung adenocarcinoma transdifferentiation to small cell lung cancer

Ishioka K., Yasuda H., Hamamoto J., Terai H., Emoto K., Kim T.J., Hirose S., Kamatani T., Mimaki S., Arai D., Ohgino K., Tani T., Masuzawa K., Manabe T., Shinozaki T., Mitsuishi A., Ebisudani T., Fukushima T., Ozaki M., Ikemura S., Kawada I., Naoki K., Nakamura M., Ohtsuka T., Asamura H., Tsuchihara K., Hayashi Y., Hegab A.E., Kobayashi S.S., Kohno T., Watanabe H., Ornitz D.M., Betsuyaku T., Soejima K., Fukunaga K.

Cancer Research (Cancer Research) 81 ( 14 ) 3916 - 3929 2021.07

ISSN 00085472

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC.

Access to Document (DOI)

Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening

Ebisudani T., Sugimoto S., Haga K., Mitsuishi A., Takai-Todaka R., Fujii M., Toshimitsu K., Hamamoto J., Sugihara K., Hishida T., Asamura H., Fukunaga K., Yasuda H., Katayama K., Sato T.

Cell Reports (Cell Reports) 35 ( 10 ) 109218 2021.06

Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.

Access to Document (DOI)

Trends of concerns from diagnosis in patients with advanced lung cancer and their family caregivers: A 2-year longitudinal study

Sato T., Fujisawa D., Arai D., Nakachi I., Takeuchi M., Nukaga S., Kobayashi K., Ikemura S., Terai H., Yasuda H., Kawada I., Sato Y., Satomi R., Takahashi S., Hashiguchi M.H., Nakamura M., Oyamada Y., Terashima T., Sayama K., Saito F., Sakamaki F., Inoue T., Naoki K., Fukunaga K., Soejima K.

Palliative Medicine (Palliative Medicine) 35 ( 5 ) 943 - 951 2021.05

ISSN 02692163

Background: Both advanced cancer patients and their family caregivers experience distress and have a range of concerns after cancer diagnosis. However, longitudinal studies on this topic have been lacking. Aim: To investigate concerns in both patients with advanced lung cancer and their family caregivers longitudinally from diagnosis. Design: A multi-center prospective questionnaire-based study. Setting/participants: We recruited patients with newly diagnosed advanced lung cancer and their family caregivers at 16 hospitals in Japan. We prospectively assessed the prevalence of their concerns using the Concerns Checklist and investigated the associations between their concerns and mental status as well as quality of life until 24 months after diagnosis. Results: A total of 248 patients and their 232 family caregivers were enrolled. The prevalence of serious concerns was highest at diagnosis (patients: 68.3%, family caregivers: 65.3%). The most common serious concern was concern about the future in both groups at diagnosis (38.2% and 40.5%, respectively) and this remained high in prevalence over time, while the high prevalence of concern about lack of information improved 3 months after diagnosis in both groups. Approximately one-third of patient-family caregiver dyads had discrepant reports of serious concerns. The presence of serious concerns was significantly associated with anxiety and depression continuously in both groups. Conclusions: The majority of advanced lung cancer patients and their family caregivers have serious concerns from diagnosis, which is associated with their psychological distress. The spectrum of concerns alters over the disease trajectory, warranting efficient tailored care and support for both groups immediately after diagnosis.

Access to Document (DOI)

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.

Watanabe S, Goto Y, Yasuda H, Kohno T, Motoi N, Ohe Y, Nishikawa H, Kobayashi SS, Kuwano K, Togashi Y

Thoracic cancer 2021.01

ISSN 1759-7706

Access to Document (DOI)

Functional dissection of the KRAS G12C mutation by comparison among multiple oncogenic driver mutations in a lung cancer cell line model

Kobayashi K., Terai H., Yasuda H., Hamamoto J., Hayashi Y., Takeuchi O., Mitsuishi Y., Masuzawa K., Manabe T., Ikemura S., Kawada I., Suzuki Y., Soejima K., Fukunaga K.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 534 1 - 7 2021.01

ISSN 0006291X

© 2020 The Authors The development of molecular targeted therapy has improved clinical outcomes in patients with life-threatening advanced lung cancers with driver oncogenes. However, selective treatment for KRAS-mutant lung cancer remains underdeveloped. We have successfully characterised specific molecular and pathological features of KRAS-mutant lung cancer utilising newly developed cell line models that can elucidate the differences in driver oncogenes among tissues with identical genetic backgrounds. Among these KRAS-mutation-associated specific features, we focused on the IGF2-IGF1R pathway, which has been implicated in the drug resistance mechanisms to AMG 510, a recently developed selective inhibitor of KRAS G12C lung cancer. Experimental data derived from our cell line model can be used as a tool for clinical treatment strategy development through understanding of the biology of lung cancer. The model developed in this paper may help understand the mechanism of anticancer drug resistance in KRAS-mutated lung cancer and help develop new targeted therapies to treat patients with this disease.

Access to Document (DOI)

Basic Understandings of EGFR-mutated Lung Cancer and Its Clinical Applications

Yasuda H.

Japanese Journal of Lung Cancer (Japanese Journal of Lung Cancer) 61 ( 7 ) 911 - 918 2021

ISSN 03869628

In 2004, several groups reported the correlation between EGFR mutations and sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since then, multiple EGFR-TKIs have been developed, improving the prognosis of advanced EGFR-mutated lung cancer patients. However, most patients with advanced EGFR mutation-positive lung cancer die of lung cancer in less than five years, highlighting the need for the further development of effective therapies. To develop effective inhibitors or treatment strategies, a basic understanding of EGFR-mutated lung cancer is essential. In particular, the knowledge of how EGFR mutations activate EGFR kinase and how sensitivity to EGFR-TKIs is determined is important. In this review, I will summarize the knowledge and propose clinical insight on how to translate this basic knowledge into a clinical setting.

Access to Document (DOI)

An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Kawasaki K, Toshimitsu K, Matano M, Fujita M, Fujii M, Togasaki K, Ebisudani T, Shimokawa M, Takano A, Takahashi S, Ohta Y, Nanki K, Igarashi R, Ishimaru K, Ishida H, Sukawa Y, Sugimoto S, Saito Y, Maejima K, Sasagawa S, Lee H, Kim HG, Ha K, Hamamoto J, Fukunaga K, Maekawa A, Tanabe M, Ishihara S, Hamamoto Y, Yasuda H, Sekine S, Kudo A, Kitagawa Y, Kanai T, Nakagawa H, Sato T

Cell 2020.10

ISSN 0092-8674

Access to Document (DOI)

SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells.

Terai H, Hamamoto J, Emoto K, Masuda T, Manabe T, Kuronuma S, Kobayashi K, Masuzawa K, Ikemura S, Nakayama S, Kawada I, Suzuki Y, Takeuchi O, Suzuki Y, Ohtsuki S, Yasuda H, Soejima K, Fukunaga K

Molecular cancer research : MCR 2020.10

ISSN 1541-7786

Access to Document (DOI)

Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study.

Ishii M, Terai H, Kabata H, Masaki K, Chubachi S, Tateno H, Nakamura M, Nishio K, Koh H, Watanabe R, Ueda S, Terashima T, Suzuki Y, Yagi K, Miyao N, Minematsu N, Inoue T, Nakachi I, Namkoong H, Okamori S, Ikemura S, Kamata H, Yasuda H, Kawada I, Hasegawa N, Fukunaga K, Keio COVID-19 Research Consortium (K-CORC) and the Keio Donner Project Team.

The Journal of infection 2020.09

ISSN 0163-4453

Access to Document (DOI)

Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.

Kakimi K, Matsushita H, Masuzawa K, Karasaki T, Kobayashi Y, Nagaoka K, Hosoi A, Ikemura S, Kitano K, Kawada I, Manabe T, Takehara T, Ebisudani T, Nagayama K, Nakamura Y, Suzuki R, Yasuda H, Sato M, Soejima K, Nakajima J

Journal for immunotherapy of cancer 8 ( 2 ) 2020.09

Access to Document (DOI)

Abstract 365: The role of protein fucosylation in lung cancer progression

Keita Masuzawa, Hiroyuki Yasuda, Atsushi Matsuda, Hideki Terai, Yuki Sugiura, Junko Hamamoto, Daisuke Arai, Shizuko Kagawa, Katsura Emoto, Shinnosuke Ikemura, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga

Tumor Biology (American Association for Cancer Research) 80 ( 16_Supplement ) 365 - 365 2020.08

ISSN 0008-5472

Abstract

Lung cancer is the leading cause of cancer-associated deaths worldwide. Metabolic reprogramming facilitates the growth advantage of cancer cells and is a hallmark of cancer. Although multiple studies have investigated the cancer-specific metabolic status of lung cancer, it remains unclear. Aberrant fucosylation, which results from the deficiency or overexpression of fucosyltransferases, is also associated with a variety of cancers, including lung cancer. However, the role and regulatory mechanism(s) of fucosylation in lung cancer remain largely unknown. In order to elucidate the specific metabolic status of human lung cancer tissues, we performed metabolomics profiling of paired tumor and normal tissues from patients with non-small cell lung cancer (NSCLC) using both capillary electrophoresis mass-spectrometry (CE-MS) and imaging mass-spectrometry (I-MS). We used principle component analysis (PCA) to confirm that human lung cancer has distinctive metabolic patterns. We revealed upregulation of the GDP-L-fucose de novo pathway, which regulates the level of fucosylated glycoproteins, in lung cancer tissues compared to the adjacent non-malignant lung tissues. In order to elucidate the mechanisms by which fucosylation is increased in lung cancer tissues, gene expression of fucosyltransferases (FUT1-9) were evaluated. We confirmed that fucosyltransferase 3 (FUT3) expression was increased in a significant proportion of human primary lung adenocarcinoma samples and was correlated with sLeX expression. A fucosylation inhibitor, 6-alkynyl-fucose, inhibited the proliferation and invasion of lung cancer cell lines with high endogenous FUT3 expression in vitro. Exogenous FUT3-overexpressing lung cancer cells did not show increased proliferation, but showed significantly increased invasion and adhesion activities in vitro. In order to confirm whether FUT3 promoted metastasis of A549 cells in an experimental lung metastatic mouse model, A549 lung cancer cells expressing EGFP (A549-EGFP) and A549 lung cancer cells overexpressing FUT3 (A549-FUT3) were intravenously administered to BALB/C nude mice and the numbers of metastatic nodules in the lungs were counted after 8 weeks. In concordance with our observations in vitro, there was no significant difference in tumor growth between the A549-EGFP and A549-FUT3 treatments in vivo. Interestingly, injection of A549-FUT3 resulted in an increase in the number of lung metastases compared to the injection of A549-EGFP, suggesting that FUT3 is a positive regulator of cancer invasion and metastasis. Furthermore, high expression of FUT3 in lung cancer tissues predicted a poorer prognosis for patients with lung adenocarcinoma. These findings highlight the important roles of protein fucosylation in lung cancer progression and provide the preclinical rationale to target this pathway in lung cancer treatment.

Citation Format: Keita Masuzawa, Hiroyuki Yasuda, Atsushi Matsuda, Hideki Terai, Yuki Sugiura, Junko Hamamoto, Daisuke Arai, Shizuko Kagawa, Katsura Emoto, Shinnosuke Ikemura, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga. The role of protein fucosylation in lung cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 365.

Access to Document (DOI)

Correction: EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas.

Jorge SE, Lucena-Araujo AR, Yasuda H, Piotrowska Z, Oxnard GR, Rangachari D, Huberman MS, Sequist LV, Kobayashi SS, Costa DB

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 9 ) 2277 2020.05

ISSN 1078-0432

Access to Document (DOI)

IGF2 Autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in Lung Cancer

Manabe T., Yasuda H., Terai H., Kagiwa H.D.A., Hamamoto J., Ebisudani T., Kobayashi K., Masuzawa K., Ikemura S., Kawa I.D.A., Hayashi Y., Fukui K., Horimoto K., Fukunaga K., Soeji K.M.A.

Molecular Cancer Research (Molecular Cancer Research) 18 ( 4 ) 549 - 559 2020.04

ISSN 15417786

© 2020 American Association for Cancer Research. EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a thirdgeneration EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-Autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level.

Access to Document (DOI)

　 Previous page - Next page 　