Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck.

Tim N Beck,John A Ridge,John Kaczmar,Cara Dubyk,Anna Nikonova,Barbara Burtness,Ilya G Serebriiskii,Miriam Lango,Elizabeth Handorf,Erica A Golemis,Ranee Mehra,Suraj Peri

doi:10.18632/oncotarget.4321

Abstract

Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.

Highlights

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer globally [1]
While genomic profiling of tumors yields insight into tumor subclasses with distinct prognoses [49], identification of protein expression patterns is useful in cases where significant biological effects are associated with post-translational modification of functionally important proteins [41, 50]
RB1 activity has been much investigated in human papillomavirus (HPV)-positive SCCHN and cervical cancer, but less so in HPV-negative disease

Summary

Introduction

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer globally [1]. This finding suggested that measurement of phosphoT356RB1 might strongly predict RB1 activity and given the crucial role of RB1, pT356RB1 levels may be informative in terms of patient outcome for cases of HPV-negative SCCHN.

Results

Conclusion