Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck.
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.
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA.
Tim N
TN
Beck
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
John
J
Kaczmar
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Elizabeth
E
Handorf
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Anna
A
Nikonova
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Cara
C
Dubyk
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Suraj
S
Peri
Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Miriam
M
Lango
Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
John A
JA
Ridge
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Department of Biochemistry, Kazan Federal University, Kazan, Russia.
Ilya G
IG
Serebriiskii
Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Barbara
B
Burtness
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA.
Erica A
EA
Golemis
Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Ranee
R
Mehra
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000821:virology; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013912:Threonine / Q000378:metabolism
D014408:Biomarkers, Tumor; D016160:Retinoblastoma Protein; D013912:Threonine
CDK4/6; E2F; RB1; biomarkers; head and neck cancer