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Updated: Sep 13, 2025

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

Hui Lu1,2, Wenying Fu2, Yiqun Xia3

  • 1Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China.

Cell Death Discovery
|August 1, 2025
PubMed

Insights

Adagrasib, a KRASG12C inhibitor, shows antitumor effects beyond KRASG12C mutations by downregulating NRF2 and increasing ROS. Combining adagrasib with panobinostat enhances its efficacy in cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Adagrasib is approved for KRASG12C-mutated non-small cell lung cancer.
  • Its precise antitumor mechanisms, especially off-target effects, require elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms of adagrasib's antitumor activity.
  • To explore potential synergistic effects with other agents.

Main Methods:

  • Cell viability assays on KRASG12C and non-KRASG12C cell lines.
  • Western blotting to assess protein levels (NRF2, AKT).
  • Measurement of reactive oxygen species (ROS) and autophagic flux.
  • In vitro and in vivo combination studies with panobinostat.

Main Results:

  • Adagrasib inhibited cell growth in both KRASG12C and non-KRASG12C cell lines.
  • Adagrasib treatment reduced NRF2 levels via ubiquitination, which mediated adagrasib-induced cell death.
  • Adagrasib increased cellular ROS, activating autophagy and AKT signaling.
  • Combination therapy with panobinostat showed enhanced antitumor activity.

Conclusions:

  • Adagrasib exhibits off-target effects by downregulating NRF2 and increasing ROS, activating autophagy and AKT pathways.
  • This novel mechanism provides insights into adagrasib's broader antitumor potential.
  • Combination with panobinostat represents a promising therapeutic strategy.

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