Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

Cell Commun Signal. 2024 Jan 17;22(1):45. doi: 10.1186/s12964-023-01260-8.

Abstract

Objectives: Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood.

Methods: We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved.

Results: We firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status in TP53-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent.

Conclusions: Transformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer. Video Abstract.

Keywords: Drug resistance; EGFR-TKI therapy; Myc inhibitor; SMAD4; Small-cell transformation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / pathology
  • Mutation / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Retinoblastoma Binding Proteins / genetics
  • Smad4 Protein / genetics
  • Small Cell Lung Carcinoma* / drug therapy
  • Small Cell Lung Carcinoma* / genetics
  • Small Cell Lung Carcinoma* / pathology
  • Ubiquitin-Protein Ligases / genetics

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • EGFR protein, human
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Smad4 Protein
  • SMAD4 protein, human
  • Ubiquitin-Protein Ligases