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Transformation from EGFR-mutant lung adenocarcinoma to small-cell lung cancer: from clonal evolution to lineage
Haoxin Wang1, Nan Gao1, Lu Wang1
1Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
Abstract:
EGFR-mutant lung adenocarcinoma (LUAD) that transforms into small-cell lung cancer (SCLC) following targeted therapy represents a clinically significant mechanism of acquired resistance, occurring in approximately 3-14 % of cases. This transformed variant, referred to as SCLC after transformation (SCLC-AT), follows an aggressive clinical course and carries a poor prognosis. SCLC-AT retains the original EGFR mutation but significantly down-regulates EGFR protein expression, eliminating its dependence on EGFR signaling while simultaneously acquiring a neuroendocrine phenotype. In nearly all cases, bi-allelic inactivation of both TP53 and RB1 is observed. In this overview, we provide a detailed examination of the molecular mechanisms underlying the transition from EGFR-mutant LUAD to SCLC. By integrating two primary biological concepts, clonal evolution and lineage reprogramming, we examine recent advances concerning the original cell or cells involved, as well as the genetic and epigenetic reprogramming and signaling pathway changes. While the transformation to SCLC is currently considered genetically and epigenetically irreversible, preclinical interventions targeting EZH2, AURKA, and DLL3 have shown potential in reversing the neuroendocrine phenotype or improving tumor immunogenicity. Future research should utilize single-cell and spatial multi-omics technologies to develop predictive models that can facilitate the early detection of impending transformation and guide precision therapies, ultimately enhancing patient outcomes.
Insights
Lung adenocarcinoma with EGFR mutations can transform into aggressive small-cell lung cancer after treatment. This transformation involves genetic changes and a loss of EGFR dependence, leading to poor prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- EGFR-mutant lung adenocarcinoma (LUAD) can acquire resistance to targeted therapy through transformation into small-cell lung cancer (SCLC).
- This SCLC after transformation (SCLC-AT) variant presents an aggressive clinical course and poor prognosis.
- SCLC-AT retains the EGFR mutation but down-regulates EGFR protein expression, loses EGFR signaling dependence, and gains a neuroendocrine phenotype, often with biallelic TP53 and RB1 inactivation.
Purpose of the Study:
- To examine the molecular mechanisms driving the transition from EGFR-mutant LUAD to SCLC.
- To integrate clonal evolution and lineage reprogramming concepts to understand this transformation.
- To review recent advances in identifying cell origins, genetic/epigenetic reprogramming, and signaling pathway alterations.
Main Methods:
- Review of current literature integrating clonal evolution and lineage reprogramming.
- Analysis of genetic and epigenetic reprogramming events.
- Examination of signaling pathway changes during LUAD to SCLC transformation.
Main Results:
- The transformation involves clonal evolution and lineage reprogramming, leading to loss of EGFR dependence and acquisition of a neuroendocrine phenotype.
- Biallelic inactivation of TP53 and RB1 is a near-universal finding in SCLC-AT.
- Preclinical interventions targeting EZH2, AURKA, and DLL3 show potential in reversing neuroendocrine phenotype or enhancing immunogenicity.
Conclusions:
- Transformation from EGFR-mutant LUAD to SCLC is currently considered genetically and epigenetically irreversible.
- Targeting specific pathways (EZH2, AURKA, DLL3) offers potential therapeutic strategies.
- Future research using multi-omics technologies is crucial for early detection and precision therapy development to improve patient outcomes.
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