1. Academic Validation
  2. EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy

EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy

  • Cell Death Dis. 2018 Feb 15;9(3):269. doi: 10.1038/s41419-018-0302-x.
Hongwei Xia 1 Xinyu Dai 2 Huangfei Yu 2 Sheng Zhou 2 Zhenghai Fan 2 Guoqing Wei 1 Qiulin Tang 1 Qiyong Gong 3 Feng Bi 4 5
Affiliations

Affiliations

  • 1 Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China.
  • 2 Department of Medical Oncology and Cancer Center, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China.
  • 3 Department of Radiology, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China.
  • 4 Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China. bifeng@medmail.com.cn.
  • 5 Department of Medical Oncology and Cancer Center, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China. bifeng@medmail.com.cn.
Abstract

The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the Akt and MAPK pathways. While YAP knockdown hardly affected the EGFR signaling. In addition, EGF could promote the proliferation of HCC cells in a YAP-independent manner. Combined targeting of YAP and EGFR signaling by simvastatin and the EGFR signaling inhibitors, including the EGFR tyrosine kinase inhibitor (TKI) gefitinib, the Raf Inhibitor sorafenib and the MEK Inhibitor trametinib, presented strong synergistic cytotoxicities in HCC cells. Therefore, the EGFR-PI3K-PDK1 pathway could activate the YAP signaling, and the activated EGFR signaling could promote the HCC cell growth in a YAP-independent manner. Combined use of FDA-approved inhibitors to simultaneously target YAP and EGFR signaling presented several promising therapeutic approaches for HCC treatment.

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