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<p>The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes and is associated with poor prognosis. Long considered an undruggable target, KRAS has recently become actionable with the development of direct inhibitors, particularly against the G12C mutation. Our group previously reported promising efficacy and safety results for glecirasib (JAB-21822), a novel KRAS<sup><i>G12C</i></sup> inhibitor, in phase I/II trials involving solid tumors harboring KRAS<sup><i>G12C</i></sup> mutations (ClinicalTrials.gov NCT05009329, NCT05194995). Nevertheless, primary (5.61%) and acquired (9.64%) resistance were observed. This study analyzed 18 patients with advanced solid tumors harboring the KRAS<sup><i>G12C</i></sup> mutation from the JAB-21822 cohort. Longitudinal blood samples (<i>N</i> = 45) were collected at baseline, during partial response or stable disease, and at disease progression. Circulating tumor cells (CTCs) were isolated via a microfluidics platform (CTC100, Cellomics) and categorized into epithelial (E-CTCs), mesenchymal (M-CTCs), and epithelial/mesenchymal mixed (E/M-CTCs) subtypes. At progression, the proportion of E-CTCs showed a decreased trend, while that of E/M-CTCs increased significantly (<i>p</i> = 0.03). In long-term responders, the inflection points of declining M-CTC levels correlated with clinical progression and were consistent with radiographic outcomes. Baseline CTC counts &gt; 1 were associated with shorter progression-free survival (PFS; <i>p</i> = 0.046). E-CTC ≤ 1 correlated with longer PFS (<i>p</i> = 0.025), and M-CTC ≤ 1 with longer overall survival (OS; <i>p</i> = 0.033). E/M-CTC ≤ 1 showed a trend toward improved OS (<i>p</i> = 0.086). In addition, patients with &gt; 1 CTC who received local radiotherapy for progressive lesions after glecirasib targeted therapy had significantly prolonged PFS and OS compared to those who did not (<i>p</i> &lt; 0.05).</p> Graphical Abstract <p></p>

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The dynamic evolution of circulating tumor cells during glecirasib treatment predicts survival and resistance in gastrointestinal tumors with KRASG12C mutation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Lei Jiang,
  • Yiming Luo,
  • Huan Liang,
  • Xujiao Feng,
  • Yan Huang,
  • Yanyan Li,
  • Zhenghang Wang,
  • Ting Xu,
  • Heng Zou,
  • Zhi Li,
  • Lin Shen,
  • Yang Chen,
  • Weihu Wang,
  • Jian Li

摘要

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes and is associated with poor prognosis. Long considered an undruggable target, KRAS has recently become actionable with the development of direct inhibitors, particularly against the G12C mutation. Our group previously reported promising efficacy and safety results for glecirasib (JAB-21822), a novel KRASG12C inhibitor, in phase I/II trials involving solid tumors harboring KRASG12C mutations (ClinicalTrials.gov NCT05009329, NCT05194995). Nevertheless, primary (5.61%) and acquired (9.64%) resistance were observed. This study analyzed 18 patients with advanced solid tumors harboring the KRASG12C mutation from the JAB-21822 cohort. Longitudinal blood samples (N = 45) were collected at baseline, during partial response or stable disease, and at disease progression. Circulating tumor cells (CTCs) were isolated via a microfluidics platform (CTC100, Cellomics) and categorized into epithelial (E-CTCs), mesenchymal (M-CTCs), and epithelial/mesenchymal mixed (E/M-CTCs) subtypes. At progression, the proportion of E-CTCs showed a decreased trend, while that of E/M-CTCs increased significantly (p = 0.03). In long-term responders, the inflection points of declining M-CTC levels correlated with clinical progression and were consistent with radiographic outcomes. Baseline CTC counts > 1 were associated with shorter progression-free survival (PFS; p = 0.046). E-CTC ≤ 1 correlated with longer PFS (p = 0.025), and M-CTC ≤ 1 with longer overall survival (OS; p = 0.033). E/M-CTC ≤ 1 showed a trend toward improved OS (p = 0.086). In addition, patients with > 1 CTC who received local radiotherapy for progressive lesions after glecirasib targeted therapy had significantly prolonged PFS and OS compared to those who did not (p < 0.05).

Graphical Abstract