Gastric
adenocarcinoma (GAC), the most common
malignancy of the stomach, is the fourth most common and the second cause of
cancer-related death worldwide. Although HER family plays a cardinal role in
tumorigenesis of GAC,
trastuzumab is the only approved anti-HER drug for this
malignancy and development of resistance to
trastuzumab is inevitable. Additionally, single-targeted HER inhibitors have demonstrated limited activity in GAC. Hence, there is a pressing need to devise more efficacious anti-HER therapeutic strategies. Here, we examined the anti-
tumor activity of neratinb, a pan-HER inhibitor, on GAC cells. Anti-proliferative effects of
neratinib were determined using a cell proliferation assay and
crystal violet staining.
Annexin V/PI staining,
radiation therapy and anoikis resistance and wound healing assays were carried out to examine the effects of
neratinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) analyses were applied to further investigate the anti-
tumor activity of
neratinib. We found that
neratinib sensitized GAC cells to
5FU,
carboplatin and
oxaliplatin. Moreover, we found that
neratinib was synergistic with
trametinib (an approved
MEK inhibitor) and
foretinib (a c-MET inhibitor) and potentiated radio-sensitivity of GAC cells. Furthermore, we found that
neratinib diminished GAC cell proliferation along with downregulation of FOXM1 and its targets. Additionally,
neratinib induced apoptosis along with upregulation of pro-apoptotic and downregulation of anti-apoptotic genes. Treatment with
neratinib attenuated invasive ability of GAC cells as shown by reduced anoikis resistance, downregulation of EMT markers, and reduced width in scratch assay. Our findings indicate that
neratinib provides the therapeutic potential in the treatment of GAC.