Springer Science and Business Media LLC Acta Medica Okayama 2055-0294 12 1 2026 Adverse events of romidepsin versus tucidinostat for peripheral T-cell lymphoma: a pharmacovigilance study using the Japanese adverse drug event report database 48 EN Nao Takatsu Department of Pharmacy, Okayama University Hospital Jun Matsumoto Department of Pharmacy, Okayama University Hospital Yurie Oka Department of Pharmacy, Okayama University Hospital Tomonori Sakai Department of Pharmacy, Okayama University Hospital Naohiro Iwata Department of Pharmacy, Okayama University Hospital Tsukasa Higashionna Department of Pharmacy, Okayama University Hospital Tatsuaki Takeda Department of Pharmacy, Okayama University Hospital Hirofumi Hamano Department of Clinical Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshito Zamami Department of Clinical Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas with poor prognosis, particularly in patients with relapsed or refractory (R/R) disease. Romidepsin and tucidinostat are histone deacetylase inhibitors used to treat R/R PTCL. No head-to-head post-marketing surveillance studies have compared adverse events (AEs) between the two agents. In this brief report, the AE profiles of romidepsin and tucidinostat were compared using the Japanese Adverse Drug Event Report (JADER) database to facilitate their differentiation and promote the management of AEs. Methods We conducted a descriptive analysis using data from the JADER database from April 2018 to July 2025. The reported AEs for romidepsin and tucidinostat were extracted and classified according to preferred terms (PTs) and system organ classes (SOCs). Reporting odds ratios with 95% confidence intervals were calculated to compare the AE profiles between the groups. Results In total, 998,397 reports were analysed for all drugs, including 323 for romidepsin and 753 for tucidinostat. Compared with all drugs, both agents showed significant disproportionality signals in four SOCs: Blood and lymphatic system disorders; General disorders and administration site conditions; Investigations; and Neoplasms benign, malignant and unspecified. Romidepsin exhibited additional significant signals in six SOCs: Cardiac disorders, Eye disorders, Gastrointestinal disorders, Immune system disorders, Infections and infestations, and Metabolism and nutrition disorders. Direct comparison between the two agents revealed broader AE profiles for romidepsin, with AEs more frequently reported in eight SOCs, whereas tucidinostat showed AEs in only two SOCs. Romidepsin was associated with AEs more frequently reported in several PTs, including atrial fibrillation and gastrointestinal toxicities, such as constipation, tumour lysis syndrome, hepatotoxicity, and peripheral neuropathy, which was consistent with the results at the SOC level. In contrast, several significant PTs for tucidinostat were observed in General disorders and administration site conditions and Investigations. Conclusions The Japanese real-world pharmacovigilance analysis showed differences in the AE profiles between romidepsin and tucidinostat. These differences in safety profiles may be useful for treatment selection and AE management in routine clinical practice among patients with R/R PTCL. Further studies are warranted to confirm these findings and better characterise the safety profiles of these agents. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2190-5991 17 2 2026 Muscle Atrophy-Related Adverse Events of Antidiabetic Drug Classes: A Pharmacovigilance Analysis Using VigiBase Data e70251 EN Shiho Ueta Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Takahiro Niimura Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Mitsuhiro Goda Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Tomoaki Ishida Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University Naohiro Iwata Department of Pharmacy, Okayama University Hospital Tatsuaki Takeda Department of Pharmacy, Okayama University Hospital Kei Kawada Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Koji Miyata Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Fuka Aizawa Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Kenta Yagi Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Hirofumi Hamano Department of Pharmacy, Okayama University Hospital Masayuki Chuma Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University Yuki Izawa‐Ishizawa Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Yoshito Zamami Department of Pharmacy, Okayama University Hospital Keisuke Ishizawa Department of Clinical Pharmacology and Therapeutics, University of Tokushima Graduate School of Biomedical Sciences Background: Diabetes mellitus―a chronic metabolic disorder associated with an increased risk of muscle atrophy―can significantly impact patients' quality of life and overall health outcomes. While antidiabetic medications are crucial for managing blood glucose levels, some have been linked to muscle-related adverse events, potentially exacerbating the already elevated risk of muscle deterioration in diabetic patients. However, a comprehensive analysis of muscle atrophy-related adverse events across different classes of antidiabetic drugs has been lacking. Therefore, this study investigates the profile of muscle atrophy-related adverse events across major antidiabetic drug classes using the World Health Organization's (WHO's) Individual Case Safety Reports database. Methods: A pharmacovigilance analysis was conducted using data from VigiBase, the WHO's global reporting database, from 1968 to September 2025. The study examined adverse event signals related to muscle atrophy, sarcopenia, muscular weakness and motor function decline for nine classes of antidiabetic medications. Reporting odds ratios (RORs) were calculated to assess signal detection, and co-occurrence patterns of adverse events were analysed. Results: Among 41 551 306 adverse event reports, 2 095 847 were related to antidiabetic medications. Safety signals for muscle atrophy were detected with sulfonylureas (ROR: 1.2, 95% CI: 1.01–1.43, p = 0.042), GLP-1 analogues (ROR: 1.2, 95% CI: 1.02–1.41, p = 0.031) and SGLT2 inhibitors (ROR: 1.5, 95% CI: 1.19–1.78, p < 0.001). SGLT2 inhibitors also showed a signal for sarcopenia (ROR: 6.2, 95% CI: 3.71–10.3, p < 0.001). Biguanides demonstrated signals for muscular weakness (ROR: 1.6, 95% CI: 1.54–1.71, p < 0.001) and motor function decline (ROR: 1.7, 95% CI: 1.41–2.13, p < 0.001). Thiazolidinediones, glinides, DPP-4 inhibitors and alpha-glucosidase inhibitors showed no safety signals for the examined adverse events. Additionally, co-occurrence analysis revealed frequent associations between muscle atrophy and nausea/vomiting, falls and decreased appetite across different drug classes. Conclusions: These findings indicate notable differences in the profiles of muscle atrophy–related adverse events among major classes of antidiabetic drugs, suggesting that drug selection may influence the risk of muscle function decline in patients. Clinicians should consider these safety profiles when prescribing antidiabetic therapies; however, causal relationships cannot be inferred solely from pharmacovigilance data. Further studies are warranted to establish causality between antidiabetic drug use and muscle-related adverse events and to elucidate the underlying mechanisms. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0770-3198 45 5 2026 Global trends in systemic sclerosis-related mortality, 2001–2023: an epidemiological analysis using World Health Organization mortality data 2741 2748 EN Keith Pardillada Belangoy Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yoshito Nishimura Division of Haematology and Oncology, Mayo Clinic, Rochester Ko Harada Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Quynh Thi Vu Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Hanane Ouddoud Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Judah Israel Ong Lescano Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Michio Yamamoto Graduate School of Human Sciences, The University of Osaka Tatsuaki Takeda Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University Hirofumi Hamano Department of Pharmacy, Okayama University Hospital Toshihiro Koyama Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yoshito Zamami Department of Pharmacy, Okayama University Hospital Objectives This study aimed to evaluate the global trends in systemic sclerosis (SSc)-related mortality by age, sex, and geographic region. SSc is a multisystem autoimmune disease characterized by tissue fibrosis, vascular dysfunction, and multi-organ involvement, which is associated with a high mortality risk. Methods Using the World Health Organization Mortality Database, we examined trends in SSc-related crude mortality rates (SSc-CRs) and age-standardized mortality rates (SSc-ASMR) per 1,000,000 population from 2001 to 2023. Locally weighted regression was applied to visualize long-term patterns, and Joinpoint regression was used to assess the national trends from 2010 to 2023. Results Across 74 countries, 85,291 SSc-related deaths were reported, with 79.41% occurring in females. The SSc-CR steadily increased from 1.97 (95% confidence interval [CI]: 1.71–2.23) in 2001 to 2.34 (95% CI: 2.01–2.68) in 2023, while the SSc-ASMR decreased from 1.58 (95% CI: 1.42–1.74) to 1.29 (95% CI: 1.08–1.50), respectively. Regionally, mortality was the highest in the Western Pacific region and declined in the Americas and Europe, with temporal fluctuations. The SSc-ASMR was highest in countries with a middle sociodemographic index (SDI). Conclusions While overall age-standardized mortality from SSc has declined in many regions, disparities persist. These results underscore the importance of sustaining research and enhancing disease awareness, as well as developing strategies to reduce mortality in high-risk populations and regions. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 2210-7703 46 2 2024 A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases 536 541 EN Tatsuaki Takeda Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University Shiho Sugimoto Department of Personalized Medicine and Preventive Healthcare Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Matsumoto Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University Naohiro Iwata Department of Pharmacy, Okayama University Hospital Akihiko Nakamoto Department of Pharmacy, Okayama University Hospital Aya Fukuma Ozaki Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California Hirofumi Hamano Department of Pharmacy, Okayama University Hospital Noritaka Ariyoshi Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University Yoshito Zamami Department of Pharmacy, Okayama University Hospital Background Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. Aim We analysed two real-world databases, the World Health Organization’s VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. Method Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. Results Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. Conclusion This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0300-8177 478 8 2022 Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma 1779 1790 EN Jun Matsumoto Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Anzu Nishimoto Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shogo Watari Department of Urology, National Hospital Organization Okayama Medical Center Hideo Ueki Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Shoya Shiromizu Department of Pharmacy, Okayama University Hospital Naohiro Iwata Department of Pharmacy, Okayama University Hospital Tatsuaki Takeda Department of Pharmacy, Okayama University Hospital Soichiro Ushio Department of Pharmacy, Okayama University Hospital Makoto Kajizono Department of Pharmacy, Okayama University Hospital Masachika Fujiyoshi Department of Pharmacy, Tottori University Hospital Toshihiro Koyama Department of Pharmaceuticals Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Motoo Araki Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Koichiro Wada Department of Urology, Faculty of Medicine, Shimane University Yoshito Zamami Department of Pharmacy, Okayama University Hospital Yasutomo Nasu Department of Urology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Noritaka Ariyoshi Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2022 2022 Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast EN Kosuke Ochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yin Min Thu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumiaki Takatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shimpei Tsudaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuaki Takeda Departments of Pharmacy, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshiharu Okamoto Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 23 2021 YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development 12809 EN Miwa Fujihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tatsuaki Takeda Departments of Pharmacy, Okayama University Hospital Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tomoka Mamori Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yusuke Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ryo Yoshioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Maya Uno Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yoko Suzuki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Abe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Minami Hatono Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takahiro Tsukioki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Takahashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Mariko Kochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takayuki Iwamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Naruto Taira Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Hiroyoshi Doihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1. No potential conflict of interest relevant to this article was reported.

Academic Press Acta Medica Okayama 0006-291X 529 3 2020 Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer 760 765 EN Kosuke Ochi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Kazuhiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jui Takano Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shunsaku Miyauchi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Miura Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Araki Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaomi Yamane Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuo Azuma Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Yoshiharu Okamoto Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Shinichi Toyooka Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. Materials and methods A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. Results TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. Conclusion Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 111 3 2019 YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers 849 856 EN Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shunsaku Miyauchi Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Miura Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Namba Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome. No potential conflict of interest relevant to this article was reported.