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<p>Kirsten rat sarcoma viral oncogene (KRAS) G12C inhibitors have demonstrated clinical efficacy against <i>KRAS</i> G12C–mutant non-small cell lung cancer (NSCLC); however, intrinsic and acquired resistance limit their therapeutic potential. Therefore, combination strategies are needed to address these limitations. While various combination regimens are currently being tested in clinical trials, treatments tailored to specific biomarkers remain underexplored. In this study, intrinsic and acquired KRAS G12C inhibitor–resistant tumor cells were established using patient-derived xenograft (PDX) and mouse models. We identified that tumor cell–autocrine amphiregulin (AREG)-mediated epidermal growth factor receptor (EGFR) phosphorylation plays a pivotal role in both intrinsic and acquired resistance to KRAS inhibitors. Notably, the same resistance mechanism was observed in central nervous system metastatic recurrence in a leptomeningeal carcinomatosis mouse model. RNAscope in situ hybridization detected <i>AREG</i> mRNA in tumor tissues and may serve as a diagnostic tool for assessing <i>AREG</i> expression. Furthermore, combining KRAS inhibitors with EGFR tyrosine kinase inhibitors suppressed tumor growth, effectively overcoming resistance. Notably, high <i>AREG</i> mRNA expression was observed in three of nine tumor samples from patients harboring the <i>KRAS</i> G12C mutation, including two patients who exhibited a poor response to sotorasib and one patient who achieved a partial response. In conclusion, AREG-mediated EGFR activation is a key driver of resistance to KRAS inhibitors in patients with <i>KRAS</i> G12C<i>–</i>mutant NSCLC. Combining EGFR and KRAS inhibition represents a promising strategy to overcome therapeutic resistance and may enhance and prolong clinical benefit in patients.</p>

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Amphiregulin-mediated EGFR activation drives both intrinsic and acquired resistance to KRAS G12C inhibitors in KRAS G12C–mutant non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Yifeng Liu,
  • Shigeki Nanjo,
  • Yuya Murase,
  • Sachiko Arai,
  • Satoshi Watanabe,
  • Takeshi Tsuda,
  • Junya Suzuki,
  • Hirokazu Taniguchi,
  • Kazuhiko Shibata,
  • Shigeki Sato,
  • Tsukasa Ueda,
  • Shunichi Nomura,
  • Takahiro Shimizu,
  • Koji Fukuda,
  • Hayato Koba,
  • Takafumi Kobayashi,
  • Yuichi Tambo,
  • Kenta Yamamura,
  • Noriyuki Ohkura,
  • Miki Abo,
  • Kazuyoshi Hosomichi,
  • Seiji Yano

摘要

Kirsten rat sarcoma viral oncogene (KRAS) G12C inhibitors have demonstrated clinical efficacy against KRAS G12C–mutant non-small cell lung cancer (NSCLC); however, intrinsic and acquired resistance limit their therapeutic potential. Therefore, combination strategies are needed to address these limitations. While various combination regimens are currently being tested in clinical trials, treatments tailored to specific biomarkers remain underexplored. In this study, intrinsic and acquired KRAS G12C inhibitor–resistant tumor cells were established using patient-derived xenograft (PDX) and mouse models. We identified that tumor cell–autocrine amphiregulin (AREG)-mediated epidermal growth factor receptor (EGFR) phosphorylation plays a pivotal role in both intrinsic and acquired resistance to KRAS inhibitors. Notably, the same resistance mechanism was observed in central nervous system metastatic recurrence in a leptomeningeal carcinomatosis mouse model. RNAscope in situ hybridization detected AREG mRNA in tumor tissues and may serve as a diagnostic tool for assessing AREG expression. Furthermore, combining KRAS inhibitors with EGFR tyrosine kinase inhibitors suppressed tumor growth, effectively overcoming resistance. Notably, high AREG mRNA expression was observed in three of nine tumor samples from patients harboring the KRAS G12C mutation, including two patients who exhibited a poor response to sotorasib and one patient who achieved a partial response. In conclusion, AREG-mediated EGFR activation is a key driver of resistance to KRAS inhibitors in patients with KRAS G12C–mutant NSCLC. Combining EGFR and KRAS inhibition represents a promising strategy to overcome therapeutic resistance and may enhance and prolong clinical benefit in patients.