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<p>A 62-year-old woman with <i>EGFR</i> exon 19-mutant lung adenocarcinoma developed resistance to osimertinib after 13&#xa0;months of treatment. At progression, genetic analysis revealed persistence of the <i>EGFR</i> mutation and acquisition of a <i>TPM3–NTRK1</i> fusion. Cells from the pleural effusion at this stage were cultured and established as a continuous cell line, LUNK1. LUNK1 cells displayed epithelial characteristics, with a population doubling time of 57.66&#xa0;h in vitro and 100% tumorigenicity in vivo. Xenograft histopathology showed poorly differentiated lung adenocarcinoma exhibiting solid, acinar, and micropapillary patterns. Immunohistochemistry confirmed positivity for CK7, TTF-1, Napsin A, EGFR, and pan-TRK. <i>EGFR</i> exon 19 deletion and <i>TPM3–NTRK1</i> fusion were confirmed by whole-exome and RNA sequencing, respectively, and further validated by PCR and Sanger sequencing. Drug sensitivity assays revealed an IC₅₀ of 64.0&#xa0;nM for entrectinib and 806.8&#xa0;nM for osimertinib, indicating reduced sensitivity to EGFR inhibition. <i>NTRK1</i> knockdown significantly increased osimertinib sensitivity (124.5–264.5 fold) and reduced entrectinib sensitivity (8.7–19.0 fold), suggesting <i>NTRK1</i> as a key regulator of drug response. We provided experimental evidence for that <i>TPM3–NTRK1</i> fusions can mediate acquired resistance to osimertinib in a new lung adenocarcinoma cell line. LUNK1 represents a useful preclinical model for investigating resistance mechanisms and assessing dual-targeted treatment strategies.</p>

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TPM3–NTRK1 fusion confers resistance to osimertinib in lung adenocarcinoma: a model in a continuous cell line

  • 期刊论文

  • 发表日期：

    2025年10月28日

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  • Fang Cao,
  • Jiayin Dai,
  • Kun Dong,
  • Zhenli Yang,
  • Yanli Zhu,
  • Changsong Qi,
  • Dongmei Lin,
  • Xiaocui Bian,
  • Yuqin Liu

摘要

A 62-year-old woman with EGFR exon 19-mutant lung adenocarcinoma developed resistance to osimertinib after 13 months of treatment. At progression, genetic analysis revealed persistence of the EGFR mutation and acquisition of a TPM3–NTRK1 fusion. Cells from the pleural effusion at this stage were cultured and established as a continuous cell line, LUNK1. LUNK1 cells displayed epithelial characteristics, with a population doubling time of 57.66 h in vitro and 100% tumorigenicity in vivo. Xenograft histopathology showed poorly differentiated lung adenocarcinoma exhibiting solid, acinar, and micropapillary patterns. Immunohistochemistry confirmed positivity for CK7, TTF-1, Napsin A, EGFR, and pan-TRK. EGFR exon 19 deletion and TPM3–NTRK1 fusion were confirmed by whole-exome and RNA sequencing, respectively, and further validated by PCR and Sanger sequencing. Drug sensitivity assays revealed an IC₅₀ of 64.0 nM for entrectinib and 806.8 nM for osimertinib, indicating reduced sensitivity to EGFR inhibition. NTRK1 knockdown significantly increased osimertinib sensitivity (124.5–264.5 fold) and reduced entrectinib sensitivity (8.7–19.0 fold), suggesting NTRK1 as a key regulator of drug response. We provided experimental evidence for that TPM3–NTRK1 fusions can mediate acquired resistance to osimertinib in a new lung adenocarcinoma cell line. LUNK1 represents a useful preclinical model for investigating resistance mechanisms and assessing dual-targeted treatment strategies.