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<p><i>KRAS</i> mutations are prevalent in lung adenocarcinoma (LUAD). Although KRAS-targeted therapies such as KRAS-G12C inhibitor sotorasib are now clinically available, their durability is limited by rapid resistance development, underscoring the need for novel strategies. Through high-throughput drug screening, we identified Aurora kinase (AURK) inhibitors as potent enhancers of afatinib efficacy in <i>KRAS</i> mutant LUAD models. ERBB/AURK co-inhibition synergized to suppress cell viability, clonogenicity, and tumor growth, mediated by induction of apoptosis, G<sub>2</sub> → M cell cycle arrest, and disruption of compensatory signaling pathways. Mechanistically, dual inhibition activated pro-apoptotic programs, while impairing mitotic and survival pathways, as confirmed by phospho-proteomic and transcriptomic analyses. Notably, co-targeting ERBB and AURK effectively overcame resistance in afatinib- and sotorasib-refractory models, wherein bypass activation of EGFR, ERK, and AURK was observed. Given the limited survival benefit associated with KRAS-targeted therapies and rapid emergence of resistance in clinical settings, our findings establish ERBB/AURK co-inhibition as a promising therapeutic strategy to improve durability of response and combat acquired resistance in <i>KRAS</i> driven LUAD.</p>

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KRAS mutated lung adenocarcinoma responds to pan-ERBB and Aurora kinase inhibitors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月12日

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  • Iris Z. Uras,
  • Marija V. Trkulja,
  • Abdelrahman K.A.A. Salama,
  • Jaqueline Horvath,
  • Khushi Asnani,
  • Christoph Trenk,
  • Stefan Kubicek,
  • Martin Bilban,
  • Herwig P. Moll,
  • Emilio Casanova

摘要

KRAS mutations are prevalent in lung adenocarcinoma (LUAD). Although KRAS-targeted therapies such as KRAS-G12C inhibitor sotorasib are now clinically available, their durability is limited by rapid resistance development, underscoring the need for novel strategies. Through high-throughput drug screening, we identified Aurora kinase (AURK) inhibitors as potent enhancers of afatinib efficacy in KRAS mutant LUAD models. ERBB/AURK co-inhibition synergized to suppress cell viability, clonogenicity, and tumor growth, mediated by induction of apoptosis, G2 → M cell cycle arrest, and disruption of compensatory signaling pathways. Mechanistically, dual inhibition activated pro-apoptotic programs, while impairing mitotic and survival pathways, as confirmed by phospho-proteomic and transcriptomic analyses. Notably, co-targeting ERBB and AURK effectively overcame resistance in afatinib- and sotorasib-refractory models, wherein bypass activation of EGFR, ERK, and AURK was observed. Given the limited survival benefit associated with KRAS-targeted therapies and rapid emergence of resistance in clinical settings, our findings establish ERBB/AURK co-inhibition as a promising therapeutic strategy to improve durability of response and combat acquired resistance in KRAS driven LUAD.