Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck
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Tim N. Beck1,4,*, John Kaczmar1,2,*, Elizabeth Handorf1, Anna Nikonova1, Cara Dubyk1, Suraj Peri1, Miriam Lango3, John A. Ridge3, Ilya G. Serebriiskii1,6, Barbara Burtness5, Erica A. Golemis1,4 and Ranee Mehra1,2
1 Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
2 Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
3 Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
4 Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA
5 Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA
6 Department of Biochemistry, Kazan Federal University, Kazan, Russia
* These authors contributed equally to this work and should be considered Co-first authors
Ranee Mehra, email:
Keywords: biomarkers, RB1, CDK4/6, E2F, head and neck cancer
Received: April 16, 2015 Accepted: May 22, 2015 Published: May 29, 2015
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.
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