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Review
. 2025 May 26;26(11):5096.
doi: 10.3390/ijms26115096.

Transformation to Neuroendocrine Phenotype in Non-Small-Cell Lung Carcinoma: A Literature Review

Irene Hernández de Córdoba  1 , Xabier Mielgo-Rubio  2 , Paloma Cejas  3 , Jorge Palomar Ramos  4 , Beatriz Garrido-Rubiales  1 , Sandra Falagán Martínez  1 , Gustavo Rubio Romero  1 , María Morales Parga  1 , Laura Moll Taltavull  1 , Andrea Fernández González  1 , Enrique Casado Sáenz  1 , María Sereno  1   5
Affiliations
Review

Transformation to Neuroendocrine Phenotype in Non-Small-Cell Lung Carcinoma: A Literature Review

Irene Hernández de Córdoba et al. Int J Mol Sci. .

Abstract

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum-etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients.

Keywords: Rb1; TP53; neuroendocrine transformation; non-small-cell lung cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Targeted treatment against NSCLC histology selected the SCLC clone, making it dominant.
Figure 2
Figure 2
Different mechanisms of transformation to a NE phenotype described in the context of EGFR disease.
See this image and copyright information in PMC

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