EPHA2 blockade reverses acquired resistance to afatinib induced by EPHA2‐mediated MAPK pathway activation in gastric cancer cells and avatar mice

Abstract

Afatinib is a pan‐HER inhibitor approved for specific types of lung cancer. We explored antitumor activity, predictive biomarkers and the potential mechanisms underlying antitumor effect and acquired resistance of afatinib in gastric cancer (GC) in vitro and in vivo. Five human GC cell lines and eight patient‐derived xenograft (PDX) models with clear molecular profiling were used to evaluate the antitumor activity and mechanisms of afatinib. The ErbB family and downstream PI3K/AKT/mTOR and mitogen‐activated protein kinase (MAPK) pathways were evaluated before and after afatinib treatment. An afatinib‐resistant PDX model was established to explore both the potential mechanisms of drug resistance and reversal strategies. We found that afatinib exerted a strong tumor suppression in EGFR/HER2 highly amplified (copy number >6) or overexpressed (IHC 3+) PDX models and a moderate tumor suppression in EGFR/HER2 moderately expressed (IHC 2+) PDX models. Afatinib selectively inhibited the proliferation of HER2 highly amplified GC cells in a dose‐dependent manner in vitro. Afatinib also exerted its antitumor effect by inducing cell apoptosis and cell arrest at G1 phase. Diminished activation of the ErbB family and downstream PI3K/AKT/mTOR and MAPK pathways was also observed. Erythropoietin‐producing hepatocellular receptor A2 (EPHA2) upregulation and phosphorylation might be involved in afatinib‐acquired resistance, and EPHA2 blockade could restore afatinib sensitivity. GC patients with amplification (copy number >6) or overexpression (IHC 3+) of EGFR/HER2 were most likely to benefit from afatinib treatment and EPHA2 blockade reversed acquired resistance to afatinib treatment, which could provide solid evidences for future clinical trials.

Upregulation of cystatin SN promotes hepatocellular carcinoma progression and predicts a poor prognosis

“…Y. Wang et al, 2013), and is involved in oncogenesis of various malignancies of the digestive system (Z. Chen et al, 2019;Gao et al, 2017;. In our outcomes, LY294002 was used for rescue experiments.…”

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients

“…These miRNAs exert tumor-suppressive effects by repressing oncogenes in HCC [73][74][75]. miRNA deregulation is an early event that can be detected in premalignant liver dysplastic nodules and can further accumulate during liver carcinogenesis [76][77][78][79].…”

The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma

“…EPHA2 is a member of the ephrin receptor subfamily of protein tyrosine kinases, and EFNA1 (ephrin A1) is its ligand. Recent studies considered the EPHA2 signalling pathway as a target of cancer therapy, and revealed that blocking EPHA2 reversed the acquired resistance of gastric cancer cells to afatinib and inhibit the proliferation of small cell lung cancer cells 31,32 . In ESCC, EFNA1 and EPHA2 were upregulated, and their overexpression was correlated with short overall survival in patients 17,33,34 .…”