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Updated: Dec 25, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC
Kai Zhang1, Xiaohua Hong1, Zhengbo Song2
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, P.R. China.
Purpose:
NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy.
Experimental Design:
Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCH mut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis.
Results:
Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALK WT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; P = 0.035). Del-NOTCH mut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCH mut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCH mut.
Conclusions:
This work distinguishes del-NOTCH mut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.
Insights
Deleterious NOTCH mutations predict better response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). This finding supports genomic profiling for personalized immunotherapy strategies.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- NOTCH signaling is implicated in non-small cell lung cancer (NSCLC) tumorigenesis and immune tolerance.
- This suggests a potential link between NOTCH mutations and the efficacy of immune checkpoint inhibitors (ICI).
Purpose of the Study:
- To investigate whether NOTCH mutations can serve as a predictive biomarker for immunotherapeutic response in NSCLC.
- To explore the molecular mechanisms underlying the association between NOTCH mutations and ICI efficacy.
Main Methods:
- Analysis of multi-dimensional data (genomic, transcriptomic, clinical) from internal and public NSCLC cohorts treated with ICI.
- Utilized the Polymorphism Phenotyping v2 (PolyPhen-2) system to identify deleterious NOTCH mutations (del-NOTCHmut).
- Employed CIBERSORT and gene set enrichment analysis on TCGA data to investigate molecular mechanisms.
Main Results:
- A significant correlation was found between NOTCH1/2/3 mutations and improved ICI outcomes (response rate, progression-free survival, overall survival) in the EGFR/ALK wild-type NSCLC population across multiple cohorts.
- Deleterious NOTCH mutations (del-NOTCHmut) demonstrated superior predictive value compared to non-deleterious mutations, potentially through enhanced DNA damage response and immune activation gene transcription.
- Del-NOTCHmut was independently associated with immunotherapeutic benefit but not with prognosis or chemotherapeutic response, highlighting its predictive but not prognostic utility.
Conclusions:
- Deleterious NOTCH mutations are identified as a potential predictive biomarker for favorable ICI response in NSCLC.
- Genomic profiling, specifically for NOTCH mutations, is crucial for optimizing immunotherapy selection in NSCLC.
- Results suggest the potential for personalized combination immunotherapy, such as adding NOTCH inhibitors to ICI regimens, to enhance treatment efficacy.
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