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Updated: Jun 10, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth
Antonio Gualberto1, Marisa Dolled-Filhart, Mark Gustavson
1Department of Clinical Development and Medical Affairs, Pfizer Oncology, New London, Connecticut, USA. antonio_gualberto@brown.edu
Purpose:
This study aimed to identify molecular determinants of sensitivity of non-small cell lung cancer (NSCLC) to anti-insulin-like growth factor receptor (IGF-IR) therapy.
Experimental Design:
A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), IRS-2, vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogen-activated protein kinase and Akt1 were also analyzed.
Results:
IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because no other biomarker/response interaction was observed using classical histologic subtyping, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the steps of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin intermediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several markers of the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) compared with those in the mesenchymal-like subset (32%; P = 0.03). Only one epithelial-like tumor was identified in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferentiation at diagnosis.
Conclusion:
NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.
Insights
Non-small cell lung cancer (NSCLC) exhibits molecular subtypes with varying sensitivity to insulin-like growth factor receptor (IGF-IR) therapies. Identifying these subtypes, particularly transitional ones, can guide treatment decisions for improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Non-small cell lung cancer (NSCLC) is a heterogeneous disease.
- Targeting the insulin-like growth factor receptor (IGF-IR) pathway is a therapeutic strategy for NSCLC.
- Predicting response to IGF-IR inhibition remains a challenge.
Purpose of the Study:
- To identify molecular factors influencing NSCLC sensitivity to anti-IGF-IR therapy.
- To investigate the role of various biomarkers in predicting treatment response.
- To stratify NSCLC patients based on molecular profiles for targeted therapy.
Main Methods:
- Analysis of 216 NSCLC tumor samples, including retrospective and prospective cohorts treated with figitumumab.
- Assessment of biomarkers such as IGF-IR, EGFR, IGF-II, IGF-IIR, IRS-1, IRS-2, vimentin, and E-cadherin.
- Molecular subtyping using principal component analysis and Bayesian clustering to identify epithelial-to-mesenchymal transition (EMT)-related subpopulations.
Main Results:
- IGF-IR expression varied across NSCLC histologic subtypes, with higher levels in squamous cell tumors.
- A molecular subtyping approach identified three distinct NSCLC subsets: epithelial-like, transitional, and mesenchymal-like, based on E-cadherin and IRS-1 expression.
- The transitional molecular subtype exhibited a significantly higher response rate (71%) to chemotherapy combined with figitumumab compared to the mesenchymal-like subtype (32%).
Conclusions:
- NSCLC is composed of distinct molecular subsets with differential sensitivity to IGF-IR inhibition.
- The identified molecular subtypes, particularly the transitional subset, represent potential predictive biomarkers for anti-IGF-IR therapy.
- These findings suggest a mechanism-based approach to stratify NSCLC patients for targeted IGF-IR inhibition.
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