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Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT
Published on: January 22, 2018
HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric
1Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
Background:
Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.
Methods:
Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.
Results:
Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.
Conclusions:
Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.
Insights
Targeted therapies for gastric cancer (GC) show promise. This study found human epidermal growth factor receptor 2 (HER2), MET, and fibroblast growth factor receptor 2 (FGFR2) alterations in distinct GC segments, suggesting potential benefits from MET- or FGFR2-targeted treatments for HER2-negative patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer (GC) remains a major global health challenge, with targeted therapies offering new hope.
- Understanding the molecular landscape of GC is crucial for advancing treatment strategies.
Purpose of the Study:
- To investigate the molecular segmentation of human epidermal growth factor receptor 2 (HER2), MET, and fibroblast growth factor receptor 2 (FGFR2) in gastric cancer.
- To correlate these molecular alterations with sensitivity to targeted therapies in GC cell lines and patient-derived xenografts.
- To inform future clinical trial designs by clarifying the distribution of these therapeutic targets in GC.
Main Methods:
- Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were employed to profile HER2, MET, and FGFR2 in Chinese GC samples.
- GC cell lines and patient-derived GC xenografts (PDGCX) were utilized to assess anti-tumor sensitivity to targeted inhibitors.
- Correlations between molecular alterations and drug sensitivity were analyzed.
Main Results:
- HER2, MET, and FGFR2 alterations were identified in 13.4%, 12.2%, and 5.2% of 172 GC patients, respectively.
- Co-positivity for MET and HER2 was observed in 3 patients; MET and FGFR2 co-positivity occurred in one patient with distinct cellular localization.
- In vitro sensitivity to targeted agents was observed only in cell lines with corresponding high target expression, and an MET-positive PDGCX model responded to crizotinib.
Conclusions:
- Oncogenic driver alterations in HER2, MET, and FGFR2 manifest in largely distinct molecular segments within gastric cancer.
- A substantial number of HER2-negative GC patients could potentially benefit from therapies targeting MET or FGFR2.
- This molecular segmentation aids in stratifying patients for targeted therapy clinical trials.
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