Exploring the role of molecular biomarkers as a potential weapon against gastric cancer: A review of the literature

Table 1 Showing the molecular markers used in gastric cancer pharmacogenomics

Marker type	Name	Drug predicted	Predicted drug effect
Genetic markers	13 gene signature[48]	5-FU	Sensitivity or resistance to 5-FU
Genetic markers	MRP4[49]	Cisplatin	DDP resistance
Genetic markers	Metallothionein-IG and HBEGF[25]	Cisplatin	DDP resistance
Genetic markers	Dihydropyrimidine	5-FU	5-FU resistance
	Dehydrogenase and HB-EGF-like growth factor genes[25]
Genetic markers	Panel of genes[26]	Doxorubicin	Predicts response to chemotherapy
Genetic markers	Dihydropyrimidine	5-FU	5-FU resistance
	Dehydrogenase and HB-EGF-like growth factor genes[25]
Genetic markers	TP53 codon 72 polymorphism[50]	Paclitaxel and cisplatin	Certain genotypes predict response to combination therapy
lncRNA	lncRNA MRUL[36]	Multiple chemotherapeutic drugs	Multidrug resistance
Epigenetic Markers	Methylation BMP4[38]	Cisplatin	High expression predicts resistance to the drug
Epigenetic Markers	Promoter methylation of RPRM[39]	CDDP and 5-FU	Prediction of response to treatment
Epigenetic markers	Methylation of BNIP3 and DAPK[37]	Fluoropyrimidine-based chemotherapy	Methylation predicts lower response to chemotherapy
miRNA	miRNA27a[34]	Fluoropyrimidine combined with oxaliplatin or paclitaxil	Prediction of response to treatment
MicroRNA	58 signature mi-RNA; among them: let-7g, miR-342, miR-16, miR-181, miR-1, and miR-34[33]	Cisplatin and 5-FU	Chemotherapeutic response
Protein markers	Thymidylate synthetase (TS) and Dihydropyrimidine dehydrogenase (DPD)[27,40]	5-FU	Correlation with tumor sensitivity to 5-FU
Serum protein	AMBP[41]	paclitaxel–capecitabine	Predicts response to chemotherapy
Tissue protein	FOXM1[43]	Docetaxel	Resistance to Docetaxel
Transcription factor
Protein markers	Ribosomal proteins S13 and L23[47]	vincristine, adriamycin, and 5-FU	Multidrug resistance by inhibition of chemotherapy related cell death and detoxification system
Serum protein (ELISA)	REG4[42]	5-FU	Resistance to 5-FU containing regimens
Protein markers	Class III β tubulin serum level[45,46]	Paclitaxel plus capecitabine	Prediction of response to treatment

MRP4: Multi drug resistance protein 4; HBEGF: Heparin-binding epidermal growth factor-like growth factor; DDP: Dihydropyrimidine; MRUL: MDR-related and upregulated lncRNA; CDDP: Cisplatin; DAPK: Death-associated protein kinase; AMBP: Alpha-1-microglobulin/bikunin precursor; foxm1: Forkhead box protein M1; REG4: Regenerating family member 4; 5-FU: 5-fluorouracil.

Table 2 Molecularly-targeted drugs evaluated in clinical trials for gastric cancer

Drug name	Type	Molecular effect	Primary cancer which it is used	Effect on gastric cancer in studies
Trastuzumab[17]	Fully humanized monoclonal antibody	Anti-HER-2 receptor protein	Breast cancer	Effective
				First approved molecular therapy
Sunitinib[17]	Oral multi-tyrosine kinase inhibitor	Anti- VEGF, PDGF and KIT receptors	Gastrintestinal stromal tumors, renal cell carcinoma and pancreatic neuroendocrine tumors	Limited therapeutic effect
Bevacizumab[131,132]	Fully humanized monoclonal antibody	Anti-VEGF	Colorectal cancer, non small cell lung cancer and breast cancer	Gives better survival in peritoneal metastatic disease or combined with anti-HER-2 therapy
Lapatinib[17]	Oral dual tyrosine kinase inhibitor	Anti-EGFR and HER-2	HER-2 positive advanced breast cancer	Not effective
Everolimus[17]	Oral mTOR inhibitor	Anti-intracellular receptor FKBP12	Renal cancer	Effective in advanced gastric cancer
Ramucirumab[17]	Fully humanized IgG1 monoclonal antibody	Anti-VEGFR-2	Gastric and lung cancer	Effective approved
Cetuximab[17]	Monoclonal IgG antibody	Anti-EGFR	Colorectal cancer	Not effective
Panitumumab[17]	Fully humanized IgG2 monoclonal antibody	Anti-EGFR	Advanced colorectal cancer	Not effective
Gefitinib[133]	Tyrosine kinase inhibitor	Anti- EGFR	EGFR mutation positive lung cancer	Not effective
Matuzumab[134]	Fully humanized monoclonal antibody	Anti-EGFR	Not yet approved in any other indication	Moderately effective
Tivantinib[94]	Tyrosine kinase inhibitor	Selective c-Met inhibitor	Not yet approved in any other indication	moderately effective
Onartuzumab[135]	Fully humanized monoclonal antibody	Anti-extracellulardomain of the tyrosine kinase receptor MET	Not yet approved in any other indication	Not effective
Regorafenib[73]	Tyrosine kinase inhibitor	Anti-angiogenic factor	Gastrointestinal stromal tumors	Found effective when tested on xenograft model with GC
Pembrolizumab[100]	Monoclonal antibody	PD-1 inhibitor	Advanced melanoma, advanced lung cancer	Promising phase IB results.
				Phase III results are awaited
Apatinib[72]	Tyrosine kinase inhibitor	Multikinase inhibitor	Not yet approved in any other indication	Shown to be effective in a phase III Chinese study

VEGF: Vascular endothelial growth factor; PDGF: Platelet-drived growth factor; EGFR: Epidermal growth factor receptor; mTOR: Mammalian target of rapamycin; VEGFR: VEGF receptor; MET: Mesenchymal epithelial transition; PD-1: Programmed cell death protein-1.