Molecular biology and immunology of head and neck cancer

Abstract

In recent years, our knowledge and understanding of head and neck squamous cell carcinoma (HNSCC) has expanded dramatically. New high-throughput sequencing technologies have accelerated these discoveries since the first reports of whole-exome sequencing of HNSCC tumors in 2011. In addition, the discovery of human papillomavirus in relationship with oropharyngeal squamous cell carcinoma has shifted our molecular understanding of the disease. New investigation into the role of immune evasion in HNSCC has also led to potential novel therapies based on immune-specific systemic therapies.

Trial registration: ClinicalTrials.gov NCT01697800 NCT02252042 NCT02255097.

Keywords: Head and neck cancer; Immunology; Molecular biology; Targeted therapy.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Genetic alterations in key oncogenic pathways from TCGA. (From Hayes, N et al. The Cancer Genome Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, in press. 2014, with permission.)

Figure 2. CDKN2A gene products and p53 regulation

CDKN2A codes for alternatively spliced p14ARF and p16INK4a genes. The p14 protein inhibits MDM2, which ubiquitinates p53. Both p21, induced by p53, and p16 inhibit cyclins that promote cell cycle progression through phosphorylation of retinoblastoma protein (Rb). Rb feeds back to inhibit p16 production.

Figure 3. EGFR signaling and downstream pathways

When an extracellular ligand binds to EGFR, dimerization occurs, promoting cross phosphorylation. This activates Ras signaling and activates PI3K to produce PIP3. PIP3 phosphorylates Akt which promotes mTOR signaling, promotes MDM2 (inhibits p53) and inhibits apoptosis.

Figure 4. Potential targets for therapy in head and neck cancer

SFK= Src family kinases. (Adapted from Du Y, Peyser ND, Grandis JR. Integration of molecular targeted therapy with radiation in head and neck cancer. Pharmacology & therapeutics. Apr 2014;142(1):88–98, with permission.)