Related Experiment Video
Updated: Jun 13, 2026
Ultra-Fast Amplicon-Based Next-Generation Sequencing in Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors
Judith A Gilbert1, Laura J Adhikari, Ricardo V Lloyd
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.
Insights
Neuroendocrine tumors (NETs) show potential therapeutic targets in heat shock protein 90 (Hsp90) and insulin-like growth factor 1 receptor (IGF1R). These biomarkers, along with epidermal growth factor receptor (EGFR), warrant further investigation for novel NET treatments.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Neuroendocrine tumors (NETs) are neoplasms of endocrine cells, frequently diagnosed at advanced stages with limited therapeutic options.
- The majority of patients with NETs present with advanced disease, necessitating the exploration of novel therapeutic targets.
Purpose of the Study:
- To identify potential biomarkers in neuroendocrine tumors (NETs) that are targeted by investigational anticancer drugs.
- To assess the expression and mutation status of key oncogenic pathways in NETs to guide therapeutic development.
Main Methods:
- Analysis of 104 NETs (74 cases) for mutations in EGFR, KIT, PDGFRA, and KRAS.
- Quantification of EGFR and HER-2/neu copy number using fluorescence in situ hybridization.
- Immunohistochemical analysis for EGFR, KIT, PDGFRA, SSTR5, VEGFR1, mTOR, IGF1R, Hsp90, and TGFBR1.
- In vitro studies using NET cell lines treated with Hsp90 inhibitor (17-AAG) and IGF1R/IR inhibitor (BMS-754807).
Main Results:
- NETs lacked HER2 overexpression and activating mutations in KIT and PDGFRA.
- Elevated EGFR copy number (39%) and aneusomy (20%) were observed, with rare KRAS mutations (3%).
- Hsp90, TGFBR1, IGF1R, and SSTR5 showed high expression in a significant percentage of tumors.
- 17-AAG and BMS-754807 inhibited NET cell line proliferation in vitro, with 17-AAG affecting EGFR and IGF1R levels and BMS-754807 inhibiting IGF1R phosphorylation.
Conclusions:
- Heat shock protein 90 (Hsp90), insulin-like growth factor 1 receptor (IGF1R), and epidermal growth factor receptor (EGFR) are promising targets for novel NET therapeutics.
- Further research is warranted to develop anticancer drugs targeting Hsp90 and IGF1R for specific NET patient populations.
