Molecular mechanisms and therapeutic strategies for small-cell lung cancer transformation after TKI therapy in EGFR-mutated lung adenocarcinoma (Review)

Lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations is a common subtype of non-small cell lung cancer (NSCLC). Although it responds well to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance to EGFR-TKIs inevitably occurs, which limits the use of the EGFR-TKIs. One resistance mechanism is small-cell transformation, which refers to the histological switch of EGFR-mutant lung adenocarcinoma to a small-cell lung cancer phenotype following TKI exposure. Small cell transformation is associated with a poor prognosis and requires different treatment modalities compared with NSCLC. The molecular mechanisms underlying small cell transformation are not fully elucidated, but may involve the loss of tumor suppressor genes, such as RB1 and TP53, and the activation of neuroendocrine pathways. In the present review, the current advances in the molecular characteristics and therapeutic regimens for small-cell transformation in patients with EGFR-mutated lung adenocarcinoma who are resistant to EGFR-TKIs, are summarized.