Antitumor Mechanisms of Targeting the PDK1 Pathway in Head and Neck Cancer

Abstract

G-protein-coupled receptors (GPCRs) activate the epidermal growth factor receptor (EGFR) and mediate EGFR-independent signaling pathways to promote the growth of a variety of cancers including head and neck squamous cell carcinoma (HNSCC). Identification of the common signaling mechanisms involved in GPCR-induced EGFR-dependent and independent processes will facilitate the development of more therapeutic strategies. In this study, we hypothesized that phosphoinositide-dependent kinase 1 (PDK1) contributes to GPCR-EGFR crosstalk and signaling in the absence of EGFR and suggests that inhibition of the PDK1 pathway may be effective in the treatment of HNSCC. The contribution of PDK1 to the EGFR-dependent and independent signaling in HNSCC was determined using RNAi, a kinase-dead mutant and pharmacological inhibition. In vivo xenografts studies were also performed to determine the efficacy of targeting PDK1 alone or in combination with the FDA-approved EGFR inhibitor cetuximab. PDK1 contributed to both GPCR-induced EGFR activation and cell growth. PDK1 also mediated activation of p70S6K in the absence of EGFR. Blockade of PDK1 with a small molecule inhibitor (AR-12) abrogated HNSCC growth, induced apoptosis and enhanced the anti-proliferative effects of EGFR tyrosine kinase inhibitors in vitro. HNSCC xenografts expressing kinase-dead PDK1 demonstrated increased sensitivity to cetuximab compared to vector-transfected controls. Administration of AR-12 substantially decreased HNSCC tumor growth in vivo. These cumulative results demonstrate that PDK1 is a common signaling intermediate in GPCR-EGFR crosstalk and EGFR-independent signaling, and where targeting the PDK1 pathway may represent a rational therapeutic strategy to enhance clinical responses to EGFR inhibitors in HNSCC.

HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer

“…Immunoblot analysis confirmed the higher expression of PDK1 in the HPV (-) WSU12 and UM19 cell lines (Figure 4E ). It should be noted that among the four PDK family members, PDK1 was shown to play a role in glucose metabolism in HNSCC cells [ 25 , 26 ].…”

Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway

“…21 On the basis of the important functions in tumor cells, PDK1 has been served as an effective therapeutic target for anticancer treatment. 22, 23 …”

The MID1 protein is a central player during development and in disease

“…PDPK1 induces the activity of mTOR and by stimulating the mTOR pathway induces protein translation and cell proliferation (78,79). Inhibition of PDPK1 stops tumour growth in tumours like head and neck squamous cell carcinoma (6,7). The MID1 complex binds to a specific motif within the PDPK1 mRNA, the so-called MIDAS (MID1 associates sequence) (5).…”

“…In addition, MID1 induces the translation of the mTOR activator PDPK1 (5). Inhibition of PDPK1 stops tumour growth in several tumours (6,7). In prostate cancer cells MID1 binds to the androgen receptor (AR) mRNA and induces its translation.…”