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Updated: May 24, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Quantitative Protein Expression of Antibody-Drug Conjugate Targets in EGFR Mutated and Wild-type Non-Small Cell Lung
Ioannis P Trontzas1,2, Mengni He1, Anna Wurtz3
1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Purpose:
Antibody-drug conjugates (ADC) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.
Experimental Design:
We used quantitative immunofluorescence assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, and EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation [EGFR mutated (n = 83), EGFR wild-type (n = 128), and EGFR unknown (n = 232)]. Assay limits were established by mass spectrometry on standard cell lines.
Results:
All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above the assay limits for all targets. A comparison of target expression showed a significant association of HER2 with EGFR expression and a nonsignificant association with EGFR mutation (P = 0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation but no significant association with EGFR expression (P < 0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (P = 0.047).
Conclusions:
ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status, and fully quantitative approaches may help select patients for ADC targeting. Intertarget correlation may provide an insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, quantitative immunofluorescence may be a valuable tool to select ADC treatment sequence. See related commentary by Hirsch, p. 2550.
Insights
Antibody-drug conjugates (ADCs) show broad target expression in non-small cell lung cancer (NSCLC). Quantitative immunofluorescence may help identify patients who will benefit from ADC therapy beyond mutation status.
Area of Science:
- Oncology
- Pharmacology
Background:
- Antibody-drug conjugates (ADCs) offer promise for non-small cell lung cancer (NSCLC) treatment.
- However, patient response to ADCs in NSCLC is currently limited to a small subset.
Purpose of the Study:
- To quantify the expression levels of four ADC target proteins (HER2, TROP2, HER3, EGFR) in NSCLC.
- To investigate the association between these targets and EGFR mutation status.
Main Methods:
- Quantitative immunofluorescence (QIF) assays were used to measure target protein levels.
- Three NSCLC tissue microarray cohorts were analyzed, stratified by EGFR mutation status.
- Assay limits were validated using mass spectrometry.
Main Results:
- All four ADC targets (HER2, TROP2, HER3, EGFR) showed broad expression across all NSCLC cohorts.
- HER2 expression was significantly associated with EGFR expression (p=0.0005).
- HER3 expression negatively correlated with EGFR mutation (p<0.0001), while EGFR expression associated with EGFR mutation (p=0.047).
Conclusions:
- ADC targets are highly expressed in NSCLC, suggesting potential for broader patient benefit.
- Patient selection for ADCs may extend beyond mutation status, with quantitative approaches being valuable.
- Understanding inter-target correlations can elucidate signaling pathways and resistance mechanisms.
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