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Web of Science

Language：English   Publisher：Molecular Cancer  

Background: Despite an initial favorable response of EGFR-mutant non–small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear. Methods: To identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR-mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model. Results: Transcriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model. Conclusions: Our findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR-mutant NSCLC.

DOI： 10.1186/s12943-025-02493-6

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PubMed

Language：English   Publisher：British Journal of Cancer  

Background: HER2-targeted antibody–drug conjugates (ADCs) have shown marked efficacy for HER2 mutation-positive non-small cell lung cancer (NSCLC). The intracellular trafficking of mutant HER2 has remained to be fully elucidated, however. Methods: HER2 dynamics were examined in cells expressing wild-type (WT) or mutant HER2 with the use of live cell imaging and an in situ proximity ligation assay. Proteins related to mutant HER2 trafficking were identified by liquid chromatography and tandem mass spectrometry. Results: HER2 internalization was enhanced in NSCLC cells expressing mutant HER2 compared with those expressing HER2(WT). Homodimers of HER2(WT) were localized mainly at the cell surface, whereas those of mutant HER2 were present mostly in the cytoplasm. Knockdown of EGFR or HER3 suppressed internalization of HER2(WT) but not that of mutant HER2. The enhanced internalization of mutant HER2 was mediated by clathrin-dependent endocytosis, as was reflected by increased binding of the ubiquitin ligase c-Cbl to mutant HER2 and its consequent ubiquitination, and was attenuated by treatment with zongertinib, a HER2-specific tyrosine kinase inhibitor. Conclusions: Upregulation of HER2 phosphorylation promotes internalization of mutant HER2 mediated by clathrin-dependent endocytosis, likely contributing to the efficacy of HER2-targeted ADCs in NSCLC positive for HER2 mutations. (Figure presented.)

DOI： 10.1038/s41416-025-03126-x

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PubMed

Language：English   Publisher：Cancer Immunology Immunotherapy  

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

DOI： 10.1007/s00262-025-04079-z

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PubMed

Language：English   Publisher：Respiratory Investigation  

Background: Osimertinib is a standard treatment for non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Although renal dysfunction associated with osimertinib treatment is reported to be rare, detailed information on this adverse effect is needed because cytotoxic drugs such as pemetrexed are also widely administered for NSCLC but cannot be used in individuals with renal dysfunction. Methods: We retrospectively collected clinical data including the serum creatinine concentration and estimated glomerular filtration rate (eGFR) during osimertinib treatment for 130 NSCLC patients. Results: Serum creatinine and eGFR worsened gradually during osimertinib treatment, with the median value of creatinine at the point of greatest deterioration differing significantly from that at baseline (0.93 versus 0.72 mg/dL, P < 0.01). Seventy patients (54 %) experienced worsening of the CTCAE grade for creatinine increased, with the frequency of patients with grade 1 or 2 being increased significantly (P < 0.01) at the point of greatest deterioration relative to baseline (grade 1, 46.9 % versus 14.6 %; grade 2, 14.6 % versus 0.8 %, respectively). A higher serum creatinine level at baseline was a significant risk factor for worsening of the CTCAE grade (odds ratio of 1.66, P < 0.001). The median serum creatinine and eGFR at 4 weeks after osimertinib discontinuation had improved to levels similar to those for baseline. Conclusions: Renal dysfunction occurred frequently during osimertinib treatment but was ameliorated after drug discontinuation, suggesting that, although renal function should be carefully monitored, its impairment is not likely to affect subsequent chemotherapy in most patients.

DOI： 10.1016/j.resinv.2025.03.015

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PubMed

Language：English   Publisher：エルゼビア・ジャパン(株)  

EGFR変異陽性非小細胞肺癌(NSCLC)の標準治療薬オシメルチニブによる腎機能障害を評価した。2015年1月～2024年2月に当院でオシメルチニブ単剤療法を開始したNSCLC患者の臨床記録を後ろ向きに調べた。オシメルチニブ投与中の血清クレアチニン濃度および推算糸球体濾過量(eGFR)等のデータを収集した。患者130例(年齢36～90歳、男性35.4%)を解析した。血清クレアチニン値およびeGFRはオシメルチニブ投与中に徐々に悪化し、最も悪化した時点でのクレアチニン値はベースラインより有意に不良であった(中央値0.93mg/dL対0.72mg/dL、P<0.01)。70例(54%)でクレアチニン増加のCTCAEグレードが悪化し、グレード1または2の患者の割合はベースラインより最も悪化した時点で有意に高かった(グレード1:14.6%対46.9%、グレード2:0.8%対14.6%、P<0.01)。CTCAEグレード悪化の有意な危険因子はベースラインでの血清クレアチニン高値であった(オッズ比:1.66、P<0.001)。オシメルチニブ投与中止4週間後には、血清クレアチニン値およびeGFR中央値はベースラインと同程度になった。以上より、オシメルチニブ投与中は腎機能障害が発生しやすいが、投与中止後に改善することが示唆された。

Language：English   Publisher：Respiratory Medicine Case Reports  

For patients with advanced non-small cell lung cancer (NSCLC), genetic testing is crucial to identify alterations in targetable driver genes. ROS1-tyrosine kinase inhibitors have shown efficacy against NSCLC with common ROS1 fusion genes, but the impact of rare fusion partners on therapeutic outcomes is not well understood. Here, we describe a 75-year-old female with advanced lung adenocarcinoma who was treated with crizotinib after the identification of the extremely rare MPRIP-ROS1 fusion. Despite stepwise dose reductions due to adverse effects, the patient exhibited a significant tumor response to crizotinib. The sustained response, even at reduced doses, highlights the potential for targeted therapies in managing NSCLC with MPRIP-ROS1 fusion. This case also underscores the importance of comprehensive genomic profiling using hybrid capture-based next-generation sequencing to identify rare driver gene alterations that may not be detected by conventional target sequencing-based methods.

DOI： 10.1016/j.rmcr.2025.102243

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.resinv.2024.02.001

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Thoracic Cancer  

Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.

DOI： 10.1111/1759-7714.15270

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PubMed

Language：English   Publisher：エルゼビア・ジャパン(株)  

初回治療でオシメルチニブを投与したEGFR遺伝子変異陽性非小細胞肺癌(NSCLC)患者21例を対象に、中枢神経系への転移に対するオシメルチニブの再投与の有効性を検討した。対象はオシメルチニブによる初回治療後に少なくとも1サイクル以上の化学療法を施行した患者で、オシメルチニブの初回または再投与時に他の抗癌剤を併用した症例は除外した。EGFR遺伝子変異はエクソン19欠失が13例、L858R変異が8例であった。治療効果は固形がんにおける効果判定規準であるRECISTにより評価した。21例のうち16例で標的病変を認め、オシメルチニブの再投与により8例(50%)で腫瘍径の縮小を認めた。部分奏効は1例(6.3%)で達成し、安定が7例、進行が8例であった。患者全体の無増悪生存期間中央値は3.8ヵ月、全生存期間中央値は13.9ヵ月であった。中枢神経系(CNS)への転移は8例で認め、そのうち5例は軟髄膜転移であった。CNS転移例の全奏効率は100%で、1例で完全奏効、3例で部分奏効を達成した。CNS転移病変の無増悪期間中央値は24.7ヵ月に対して非CNS病変は10.5ヵ月であった。CNS転移患者の全生存期間中央値は15.7ヵ月であった。

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2023.09.067

Authorship：Lead author  

DOI： 10.1016/j.rmcr.2019.100889

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.lungcan.2018.04.005

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.lungcan.2017.09.008

Event date： 2024.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2024.4

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Country：Japan  

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