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Histologic transformation after targeted therapy resistance in driver gene-positive NSCLC: mechanisms and therapeutic

Xinyue Li1,2, Kaibo Ding3, Dujiang Liu1,2

  • 1Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.

Therapeutic Advances in Medical Oncology
|September 4, 2025
PubMed

Insights

Drug resistance in non-small cell lung cancer (NSCLC) can lead to histological transformation into more aggressive subtypes. This review explores these transformations, their mechanisms, and treatment strategies for improved patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Targeted therapies have improved outcomes for non-small cell lung cancer (NSCLC) patients with driver mutations.
  • Drug resistance remains a significant challenge, often leading to histological transformation.
  • Transformed NSCLC subtypes exhibit increased aggressiveness and therapeutic resistance.

Purpose of the Study:

  • To systematically review histological transformation types in NSCLC post-targeted therapy resistance.
  • To elucidate the complex molecular mechanisms driving these transformations.
  • To summarize current and emerging therapeutic strategies for transformed NSCLC.

Main Methods:

  • Systematic literature review of studies on NSCLC histological transformation.
  • Analysis of molecular mechanisms including RB1/TP53 inactivation and epithelial-mesenchymal transition.
  • Review of therapeutic approaches for post-transformation NSCLC.

Main Results:

  • Histological transformation into small-cell lung cancer, large-cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma is a key resistance mechanism.
  • Molecular drivers include RB1/TP53 inactivation and epithelial-mesenchymal transition.
  • Post-transformation tumors present limited therapeutic options and a poorer prognosis.

Conclusions:

  • Histological transformation is a critical challenge in NSCLC targeted therapy resistance.
  • Understanding molecular mechanisms is crucial for developing effective treatments.
  • Personalized therapeutic strategies are needed to address the complexity of transformed NSCLC.
Keywords:
drug resistancehistologic transformationnon-small-cell lung cancertargeted therapytreatment strategy

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