Epidermal growth factor receptor regulates lineage plasticity driving transformation to small cell lung cancer.

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) is clinically and genetically heterogeneous, with concurrent RB1/TP53 mutations, indicating an increased risk of transformation into small cell lung cancer (SCLC). When tumor cells convert into a different histological subtype, they lose their dependence on the original oncogenic driver, resulting in therapeutic resistance. However, the molecular details associated with this transformation remain unclear. It has been difficult to define molecular mechanisms of neuroendocrine (NE) transformation in lung cancer due to a lack of pre- and post-transformation clinical samples. In this study, we established a NSCLC cell line with concurrent RB1/TP53 mutations and built corresponding patient-derived xenograft (PDX) models to investigate the mechanisms underlying transformation to SCLC. Studying these PDX models, we demonstrate that EGFR loss facilitates lineage plasticity of lung adenocarcinoma initiated by biallelic mutations of TP53 and RB1. Gene expression analysis of these EGFR knockout tumors revealed altered expression of neuroendocrine synapse-associated lineage genes. There is an increased expression of epigenetic reprogramming factors like Sox2 and gene associated with neural development like NTRK in these EGFR knockout tumors. These findings uncovered the role of EGFR in the acquisition of plasticity, which is the ability of a cell to substantially modify its identity and take on a new phenotype, and defined a novel landscape of potential drivers of NE transformation in lung cancer.
Competing Interests: Declaration of competing interest The authors of the above-mentioned paper have no affiliations or associations with any organization/entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)