title: EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer.
abstract: Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pT356RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. ©2016 AACR.
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Molecular and Cell Biology & Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors: Tim N
authors: TN
authors: Beck
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Department of Otolaryngology Head and Neck Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Rachel
authors: R
authors: Georgopoulos
authors: Breast Cancer Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
authors: Elena I
authors: EI
authors: Shagisultanova
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Department of Otolaryngology Head and Neck Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: David
authors: D
authors: Sarcu
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Elizabeth A
authors: EA
authors: Handorf
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Cara
authors: C
authors: Dubyk
authors: Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Miriam N
authors: MN
authors: Lango
authors: Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: John A
authors: JA
authors: Ridge
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Igor
authors: I
authors: Astsaturov
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Russia.
authors: Ilya G
authors: IG
authors: Serebriiskii
authors: Developmental Therapeutics, Yale Cancer Center, New Haven, Connecticut.
authors: Barbara A
authors: BA
authors: Burtness
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors: Ranee
authors: R
authors: Mehra
authors: Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Molecular and Cell Biology & Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania. Erica.Golemis@fccc.edu ranee.mehra@fccc.edu.
authors: Erica A
authors: EA
authors: Golemis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009367:Neoplasm Staging; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D010766:Phosphorylation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; C000606393:RB1 protein, human