NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

Abstract

Trastuzumab, a humanized antibody targeting human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Acquired resistance to trastuzumab remains a barrier to patient survival and the mechanisms underlying this are still not well understood. The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognized as a potential therapeutic target for reversing trastuzumab resistance. The aim of this study was to explore the potential role of KLK10 in trastuzumab resistance (TR) gastric cancer cells. We found that KLK10 was significantly upregulated in trastuzumab-resistant cell lines, SGC7901-TR and BGC-823-TR. In addition, down regulation of KLK10 reversed the resistance in trastuzumab resistant cells. Overexpression of KLK10 induced trastuzumab resistance, and activated the PI3K/AKT signaling pathway, while downregulation of KLK10 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effect of KLK10 on resistance was diminished. Furthermore, combination of trastuzumab and PI3K/AKT inhibitor XL147 effectively inhibited tumor growth in KLK10-overexpressing xenografts. Taken together, our findings show that KLK10 promotes trastuzumab resistance, at least in part, through the PI3K/AKT signaling pathway, suggesting that KLK10 is a potentially target to overcome trastuzumab resistance, and the combination might overcome trastuzumab resistance in KLK10-overexpressed gastric cancer patients.

Kallikrein-related peptidase (KLK10) cessation blunts colorectal cancer cell growth and glucose metabolism by regulating the PI3K/Akt/mTOR pathway

“…Similarly, aberrant elevation of KLK10 promotes cell invasion and metastasis in pancreatic ductal adenocarcinoma [13]. Analogously, KLK10 elevation enhances trastuzumab resistance in gastric cancer [12]. However, KLK10 is recognized as a putative tumor suppressor in prostate cancer as the fact that KLK10 overexpression decelerates tumor proliferation and induces cell apoptosis [15].…”

“…KLK10 was initially identified in 1996 as normal epithelial cell-specific 1 (NES1). Increasing evidence has confirmed the aberrant expression of KLK10 in several cancers, including pancreatic ductal adenocarcinoma, breast cancer, and gastric cancer [12,13]. However, abundant study substantiates the contradictive roles of KLK10 in the development of cancers by regulating cell growth, invasion, and apoptosis [13,14].…”

MiR‐10a functions as a tumor suppressor in prostate cancer via targeting KDM4A

“…Inactivation of Hippo F I G U R E 4 Overexpression of miR-10a repressed expression of YAP and its target genes. 29 Particularly, KDM4A was recently discovered to stimulate YAP transcription via recruited to the promoter of YAP gene. D, Activation of YAP promoter luciferase reporter by overexpression of KDM4A could be reversed by transfection of miR-10a mimics in 293 cells.…”

<p>A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer</p>

“…Abnormal activation of the PI3K/AKT pathway has been reported to be one of the important mechanisms of inducing drug resistance in tumor cells. 64,65 And further studies have showed that some chemotherapeutics would activate the PI3K/AKT pathway which resulted in acquired drug resistance. 66,67 So far, the mechanisms of the PI3K/AKT pathway have not been fully understood.…”