Association of amphiregulin with the cetuximab sensitivity of gastric cancer cell lines

Abstract

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.

cMET as a potential therapeutic target in gastric cancer (Review)

“…Recent clinical trials have been designed with molecular alterations of cMET, EGFR/RAS/RAF as biomarkers (56,61,84). Future clinical trials may also assess molecular derangements such as cMET mutation, K-ras amplification, EGFR and HER2 status as predictive markers (14,15,83,84,86).…”

“…cMET activation may mediate resistance to EGFR and HER2 in gastric cancer (14,15). Another study observed that the acquisition of a mutation in the MET activation loop (Y1230), destabilized the autoinhibitory conformation of MET and abrogated an important aromatic stacking interaction with the inhibitor (84).…”

“…A significant proportion of gastric cancers harbor cMET overexpression and/or gene amplification (11,12), and the aberrant signaling of cMET pathways in gastric cancer has been shown to correlate with a high tumor stage and poor prognosis (11,13). The alternative activation of the cMET pathway is considered to be an important mechanism responsible for resistance therapeutics targeting HER family members, such as HER2 and epidermal growth factor receptor (EGFR) (14,15). Recently, several cMET inhibitors have been investigated in clinical trials, and the initial results are encouraging (16,17).…”

Clinical significance of MET in gastric cancer

“…The aberrant signaling of MET by overexpression or gene amplification has been detected and correlated with tumor progression or patients' survival in GC [12][13][14][15] . Alternative activation of the MET pathway is considered an important mechanism causing resistance to treatments targeting HER family members [16,17] .…”

Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells

“…However, EGFR TKIs showed no significant clinical benefits in a phase II clinical trial in patients with SCLC (23). Indeed, the response to monoclonal EGFR antibodies can be predicted by the AREG secretion in gastric cancer cell lines (24).…”