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<p>Adagrasib, a KRASG12C inhibitor, recently received accelerated approval from the US FDA for the treatment of patients diagnosed with KRASG12C-mutated non-small cell lung cancer. Although adagrasib has demonstrated excellent clinical efficacy and good safety, the molecular mechanism underlying the antitumor activity of adagrasib remains elusive. Here, we report that adagrasib treatment markedly inhibited the growth of cells harboring the KRASG12C mutation, whereas the non-KRASG12C cell lines H1299 and PC-9 were also sensitive to adagrasib, indicating that adagrasib exerted off-target effects. Mechanism studies indicated that adagrasib treatment reduced the level of NRF2 via upregulating its ubiquitination, and NRF2 overexpression can reverse the adagrasib-induced cell death in H23 and H1299 cells. Furthermore, adagrasib treatment significantly increased the cellular ROS level and thereby activating autophagy and AKT signaling pathways in H23 and H1299 cells. Importantly, combination of adagrasib with panobinostat demonstrated enhanced antitumor activity in vitro and in vivo. Overall, our data elucidate a novel mechanism of adagrasib, which will be critical for the clinical application of adagrasib.</p>

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Panobinostat potentiates adagrasib-induced cell death by triggering autophagy in human non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Hui Lu,
  • Wenying Fu,
  • Yiqun Xia,
  • Ying Yan,
  • Chongchong Shu,
  • Yinghua Chen,
  • Chenxin Xu,
  • Peisen Zheng,
  • Xin Shen,
  • Ri Cui,
  • Peng Zou,
  • Daoyong Ni

摘要

Adagrasib, a KRASG12C inhibitor, recently received accelerated approval from the US FDA for the treatment of patients diagnosed with KRASG12C-mutated non-small cell lung cancer. Although adagrasib has demonstrated excellent clinical efficacy and good safety, the molecular mechanism underlying the antitumor activity of adagrasib remains elusive. Here, we report that adagrasib treatment markedly inhibited the growth of cells harboring the KRASG12C mutation, whereas the non-KRASG12C cell lines H1299 and PC-9 were also sensitive to adagrasib, indicating that adagrasib exerted off-target effects. Mechanism studies indicated that adagrasib treatment reduced the level of NRF2 via upregulating its ubiquitination, and NRF2 overexpression can reverse the adagrasib-induced cell death in H23 and H1299 cells. Furthermore, adagrasib treatment significantly increased the cellular ROS level and thereby activating autophagy and AKT signaling pathways in H23 and H1299 cells. Importantly, combination of adagrasib with panobinostat demonstrated enhanced antitumor activity in vitro and in vivo. Overall, our data elucidate a novel mechanism of adagrasib, which will be critical for the clinical application of adagrasib.