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

Targeted therapies have significantly improved the prognosis and productivity of non-small-cell lung cancer (NSCLC) patients carrying driver mutations, but drug resistance is inevitable. Histological transformation, an important resistance mechanism, is often manifested as transformation into small-cell lung cancer, large-cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma. The mechanisms involved are complex, including RB1/TP53 inactivation, epithelial-mesenchymal transition, and microenvironmental changes. Post-transformation tumors are often more aggressive and drug-resistant, with limited therapeutic options and poorer prognosis. In this paper, we systematically review the histological transformation types, molecular mechanisms, and therapeutic strategies of NSCLC after resistance to targeted therapy, with the aim of providing a reference for clinical decision-making and promoting the development of individualized therapy.