Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells

“…The novel ATP-competitive mTOR inhibitors (such as Ku-0063794) inhibit both mTORC1 and mTORC2 kinase activities and strongly promote autophagy in various types of cancer cells [44]. Based on this thinking, numerous studies have shown that mTOR inhibitors could overcome TKI resistance in colorectal carcinoma, NSCLC, and head and neck squamous cell carcinoma [13][14][15][16]. Consistently, in our study, the anti-proliferative and pro-apoptotic effects of erlotinib were strongly enhanced by Ku-0063794; the combination of erlotinib and Ku-0063794 overcame TKI resistance in TKIresistant NSCLC cells (Fig.…”

“…In recent years, overcoming TKI resistance remains a challenge in clinical practice, and investigation of the mechanisms involved in TKI resistance seems of great significance [10][11][12][13]. Targeting the downstream signaling cascades of activated EGFR, such as mTOR, has been revealed to be an effective way to overcome the TKI resistance in NSCLC, colorectal carcinoma, and head and neck squamous cell carcinoma [13][14][15][16].…”

“…The mTOR inhibitor rapamycin that inhibits mTORC1 but has little effect on mTORC2 showed limited clinic benefits against many types of cancers [26]. Strikingly, targeting mTORC2 with specific mTOR inhibitors antagonizes TKI resistance [13][14][15][16], suggesting the essential role of mTORC2 in chemotherapy resistance. However, the specific role of mTORC2 in EGFR TKI-resistant NSCLC cells and the underlying mechanisms still remain unknown.…”

Targeting the epithelial growth factor receptor in head and neck tumours: current status and challenges

“…Despite EGFR inhibition with targeting agents, there is experimental evidence towards parallel oncogenic signalling through G protein-coupled receptors, showing that other downstream pathways remain activated during EGFR blockade (10). Identification and targeting of mediators of the cross talk between EGFR and G protein-coupled receptors could result into tumour growth inhibition and overall improvement of outcome.…”

“…It was hypothesised that the inhibition of the mammalian target of rapamycin complex (mTOR) could improve the effects of EGFR blockade in preclinical models, given the fact that mTOR is activated by both EGFR pathways as well as G protein-coupled receptors (10). To prove the hypothesis, when erlotinib (an anti-EGFR small molecule) was combined with an mTOR inhibitor (OSI-027), a significant reduction in head and neck cancer (HNC) cell line proliferation was observed, the combined treatment demonstrating a synergistic inhibition of cell survival.…”