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E2A selectively regulates TGF-β-induced apoptosis in KRAS-mutant non-small cell lung cancer

Sergei Chuikov1, Shiva Krishna Katkam1, Zhefan Wang1,2

  • 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Molecular Oncology
|March 17, 2026
PubMed

Insights

The transcription factor E2A promotes resistance to apoptosis in KRAS-mutant non-small cell lung cancer (NSCLC). Silencing E2A restores apoptosis and enhances radiation therapy effects in NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Transforming growth factor-β (TGF-β) normally suppresses tumors by inducing apoptosis.
  • In advanced non-small cell lung cancer (NSCLC), tumor cells often lose sensitivity to TGF-β's apoptotic effects, even with intact signaling pathways.
  • The mechanisms behind this resistance, particularly in KRAS-mutant NSCLC, are not fully understood.

Purpose of the Study:

  • To identify key mediators of resistance to TGF-β-induced apoptosis in mutant KRAS-driven NSCLC.
  • To investigate the role of the transcription factor E2A in this process.
  • To explore E2A as a potential therapeutic target in NSCLC.

Main Methods:

  • Utilized NSCLC cell lines with mutant and wild-type KRAS.
  • Investigated TGF-β signaling pathways, including SMAD3.
  • Employed gene silencing techniques (siRNA) to deplete E2A and KRAS.
  • Assessed apoptosis through caspase-3 activation and mitochondrial outer membrane permeabilization.
  • Analyzed expression levels of BCL-2 family and inhibitor-of-apoptosis proteins.
  • Examined the effect of E2A silencing on radiation-induced growth inhibition.
  • Correlated E2A expression with clinical NSCLC tumor samples.

Main Results:

  • TGF-β induces E2A expression in a SMAD3-dependent manner specifically in KRAS-mutant NSCLC cells.
  • Silencing E2A restores TGF-β-induced apoptosis in KRAS-mutant NSCLC without affecting epithelial-mesenchymal transition.
  • E2A depletion triggers mitochondrial apoptosis via caspase-3 activation and modulation of apoptosis-related proteins.
  • Loss of mutant KRAS abrogates the pro-apoptotic effects of E2A silencing, confirming KRAS dependency.
  • E2A is overexpressed in lung adenocarcinoma, particularly in tumors with mutant KRAS.
  • E2A silencing enhances the growth inhibitory effects of radiation therapy in NSCLC.

Conclusions:

  • E2A acts as a context-specific suppressor of TGF-β-mediated apoptosis in KRAS-mutant NSCLC.
  • E2A is a critical mediator of resistance to TGF-β-induced apoptosis in this subset of NSCLC.
  • Targeting E2A represents a promising therapeutic strategy for mutant KRAS NSCLC, potentially enhancing responses to radiation therapy.
Keywords:
E12/E47KRASSMAD3bHLH transcription factorlung adenocarcinomaradiation therapy

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