The prognostic implications of Notch1, Hes1, Ascl1, and DLL3 protein expression in SCLC patients receiving platinum-based chemotherapy

PLoS One. 2020 Oct 26;15(10):e0240973. doi: 10.1371/journal.pone.0240973. eCollection 2020.


Objectives: The aim was to analyse the tumor expression of Notch1, Hes1, Ascl1, and DLL3 in Small-Cell Lung Cancer (SCLC) and each such biomarker's potential association with clinical characteristics and prognosis after platinum-doublet chemotherapy (PDCT).

Material and methods: The protein expression of the biomarkers was evaluated using immunohistochemistry. Patients were categorized according to their sensitivity to first line PDCT: with a Progression-free survival (PFS) ≥ 3 months after completion of treatment considered "sensitive" and < 3 months after completion of treatment considered "refractory". PFS and overall survival were computed using Kaplan-Meier curves with 95% confidence interval.

Results and conclusion: The study included 46 patients, with 21 and 25 of the patients having "sensitive" and "refractory" disease, respectively. The majority of patients had a high DLL3 expression (n = 38), while a minority had Notch 1-high expression (n = 10). The chi-square test showed that there was a statistically significant negative association between Notch1 and Ascl1 expression (p = 0.013). The overall survival for patients with Notch1- high vs. low expression was 8.1 vs. 12.4 months, respectively (p = 0.036). Notch1 expression was an independent prognostic factor in the multivariate analysis (p = 0.02). No other biomarker showed any prognostic impact in this highly selected SCLC cohort. DLL3 is highly expressed in the majority of advanced staged SCLC cases, as expected. In the same patient population, Notch1 expression might have a potential prognostic implication, by driving a non-neuroendocrine differentiation process. Given the small number of cases with Notch1 high expression, the results of this study needs to be confirmed on a larger cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Male
  • Membrane Proteins
  • Middle Aged
  • Platinum / pharmacology
  • Platinum / therapeutic use*
  • Prognosis
  • Receptor, Notch1
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / metabolism
  • Survival Analysis
  • Transcription Factor HES-1
  • Treatment Outcome


  • ASCL1 protein, human
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • DLL3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Transcription Factor HES-1
  • HES1 protein, human
  • Platinum

Grants and funding

This study was supported by grants from the Stockholm Cancer Society (#161283, #171123, #154102, #174093), the Swedish Cancer Society (CAN 2015/401; CAN 2018/597), the Stockholm County Council (#20160287, # 20180404), The Erling Persson Family Foundation and Karolinska FOUU funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.