Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.

Keywords: cetuximab; chemotherapy; head and neck squamous-cell carcinoma; immunotherapy; resistance; targeted therapy.

Figure 1

Molecular mechanisms contributing to Cetuximab resistance, in particular through alterations of the EGFR pathways, activation of bypass pathways and alterations of downstream signaling effectors. Red lines and arrows show mechanisms contributing to Cetuximab resistance, and green lines and arrows show mechanisms contributing to Cetuximab sensitivity. (CTX, Cetuximab; EGFR, Epidermal Growth Factor Receptor; RTK, Tyrosine Kinase Receptor; EMT, epithelial-mesenchymal-transition; uPAR, urokinase-type plasminogen activator receptor; STAT3, signal transducer and activator of transcription 3; PTPRS, Transmembrane Protein Tyrosine Phosphatase RPTPsigma; PTEN, phosphatase and tensin homolog; AURKA, Aurora Kinase A; AURKB, Aurora Kinase B).

Figure 2

Molecular mechanisms contributing to Cetuximab resistance through the establishment of an immunosuppressive TME. Red lines and arrows show mechanisms contributing to Cetuximab resistance, and green lines and arrows show mechanisms contributing to Cetuximab sensitivity. (EGFR, Epidermal Growth Factor Receptor; NK, Natural Killer; PD1, Programmed death 1; PDL1, Programmed Death Ligand 1; KIR, Killer Immunoglobulin-like Receptor; ADCC, Antibody-dependent cellular cytotoxicity; HLA-C, Human leukocyte antigen-C; TGF, transforming growth factor; Treg, regulatory T-cells; MDSC, Myeloid-derived suppressor cells).