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HDAC6-mediated EGFR stabilization and activation restrict cell response to sorafenib in non-small cell lung cancer cells

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Abstract

Sorafenib is a multi-targeted kinase inhibitor and has been the subject of extensive clinical research in advanced non-small cell lung cancer (NSCLC). However, sorafenib fails to improve overall survival of patients with advanced NSCLC. The molecular mechanisms that account for this phenomenon are unclear. Here we show that sorafenib treatment stabilizes epidermal growth factor receptor (EGFR) and activates EGFR pathway. Moreover, this is partly mediated by stabilization of histone deacetylase 6 (HDAC6), which has been shown to regulate EGFR endocytic trafficking and degradation. Overexpression of HDAC6 confers resistance to sorafenib in NSCLC cells. Inhibition of HDAC6 with selective inhibitors synergizes with sorafenib to kill NSCLC cells via inhibition of sorafenib-mediated EGFR pathway activation. Taken together, our findings might partly explain the failure of Phase III trial of sorafenib in improving overall survival of advanced NSCLC patients and bear possible implications for the improvement on the efficacy of sorafenib in treatment of NSCLC.

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Abbreviations

AKT:

v-akt murine thymoma viral oncogene homolog

ERK:

Extracellular signal-regulated kinase

MEK:

Mitogen-activated protein kinase kinase

Flt3:

Fms-related tyrosine kinase 3

Hsp90:

Heat-shock protein 90

PDGFR:

Platelet-derived growth factor

PI3K:

Phosphoinositide 3-kinase

PARP:

Poly ADP-ribose polymerase

Ras:

Rat sarcoma viral oncogene homolog

Raf:

Rapidly accelerated fibrosarcoma

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgments

We acknowledge Prof. Jun Zhou of Nankai University for kindly providing the HDAC6 over-expression plasmids. This work was supported by the Natural Sciences Foundation of Hubei Provience (No. 2013CFA006).

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Authors and Affiliations

  1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People’s Republic of China

    Zhihao Wang, Fang Tang & Conghua Xie

  2. Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China

    Zhihao Wang, Fang Tang & Conghua Xie

  3. Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People’s Republic of China

    Pengchao Hu

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  1. Zhihao Wang
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Correspondence to Conghua Xie.

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Wang, Z., Hu, P., Tang, F. et al. HDAC6-mediated EGFR stabilization and activation restrict cell response to sorafenib in non-small cell lung cancer cells. Med Oncol 33, 50 (2016). https://doi.org/10.1007/s12032-016-0765-5

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