Investigating the effect of combination therapy on cetuximab inhibition of epidermal growth factor receptor signalling combined with dynamin inhibition in head and neck cancer squamous cell carcinoma


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Hui Yi Chew1,Adam McCluskey2,Phillip Robinson3,Benedict Panizza4,James Wells1,Riccardo Dolcetti1,Fiona Simpson1
1The University of Queensland Diamantina Institute, Brisbane, Queensland,2Centre for Chemical Biology, Chemistry, University of Newcastle, Callaghan, NSW,3Cell Signalling Unit, Children's Medical Research Institute, University of Sydney, NSW,4Department of ENT Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in Australia and it is the sixth leading cancer worldwide. Epidermal growth factor receptor (EGFR) has been shown to play a crucial role in the pathogenesis of HNSCC. EGFR is a receptor tyrosine kinase capable of intiating signalling cascades that promote cell proliferation and survival, such as PI3K/Akt and MAPK pathway. Upon activation, EGFR undergoes dynamin dependent clathrin-mediated endocytosis and eventually gets degraded. As EGFR is involves in tumourigenesis, it has been proposed to be a therapeutic target hence leading to the development of the monoclonal antibody, cetuximab. Cetuximab’s mode of mechanisms include inhibition of signalling and inducing antibody-dependent cellular cytotoxicity (ADCC). Previous studies by Simpson Laboratory showed that by inhibiting dynamin, we could enhance ADCC in response to cetuximab. Recently, in the world’s first proof-of-mechanism trial of dynamin inhibition in human beings, we showed that receptor localisation can be altered in patients’ tumours in clinic by a dynamin inhibitor, prochlorperazine. As preclinical data for our current Phase Ib clinical trials in patients, testing a combination of prochlorperazine and cetuximab, we had to ensure that the signalling inhibition role of cetuximab would not be negatively affected in these trials.

Method

We examined the signalling changes in SCC cells when treated with a combination of dynamin inhibitor and cetuximab.

Results

We found that the combination of drugs now being used in Phase Ib trial is able to inhibit proliferative signalling in both cetuximab-sensitive and cetuximab-resistant SCC cells.

Conclusion

We showed that the combination therapy does not have adverse effect on cetuximab's role in inhibiting signalling, in fact it reinstates cetuximab signalling inhibition in resistant cells and may further help to decrease drivers of proliferation in patients' tumours. Thus the proposed combination therapy shows two separate mechanisms of resistance reversal.