Cetuximab chemotherapy resistance: Insight into the homeostatic evolution of head and neck cancer (Review)

Abstract

The complex evolution of genetic alterations in cancer that occurs in vivo is a selective process involving numerous factors and mechanisms. Chemotherapeutic agents that prevent the growth and spread of cancer cells induce selective pressure, leading to rapid artificial selection of resistant subclones. This rapid evolution is possible because antineoplastic drugs promote alterations in tumor‑cell metabolism, thus creating a bottleneck event. The few resistant cells that survive in this new environment obtain differential reproductive success that enables them to pass down the newly selected resistant gene pool. The present review aims to summarize key findings of tumor evolution, epithelial‑mesenchymal transition and resistance to cetuximab therapy in head and neck squamous cell carcinoma.

Keywords: cetuximab; drug resistance; epithelial‑mesenchymal transition; head and neck neoplasms; tumor evolution.

Figure 1.

Models of Tumor Evolution. (A) Cancer arises from a single cell and evolves linearly through the selection of mutations, resulting in a homogeneous clone with a strong selective advantage. (B) Tumors evolve in a branched fashion, with distinct mutated clones derived from the same clone but differentially selected by endogenous and external factors, resulting in high intra-tumor heterogeneity. (C) The alterations responsible for the neoplastic process are present in the first malignant cell and the subsequent mutations are neutral. (D) Several tumors exhibit complex chromosomal aberrations that occur early in the neoplastic process.

Figure 2.

EMT in Neoplastic Development and Metastasis. EMT is characterized by loss of apical-basal polarity, low expression of epithelial markers (such as E-cadherin) and expression of mesenchymal markers (including N-cadherin, vimentin, fibronectin and metalloproteinases/MMPs). The mesenchymal lineage exhibits migratory properties that allows cells to invade and metastasize. Once in a new niche, they are able to undergo MET and dedifferentiate to epithelial tissues. MET, mesenchymal-epithelial transition; EMT, epithelial-mesenchymal transition; MMP, matrix metalloproteinase; ZEB1, zinc finger E-box binding homeobox 1; TWIST, twist family bHLH transcription factor.

Figure 3.

EGFR Signaling Transduction and Downstream Effectors. (A) EGFR is a receptor tyrosine kinase that possesses an extracellular ligand-binding region and a cytoplasmatic kinase domain connected by a transmembrane domain. CTX is a chimeric human/mouse monoclonal antibody that binds to domain III of the receptor blocking binding of natural ligands. (B) Binding of the EGFR ligands promotes a conformational change that facilitates homo- or heterodimerization, inducing (C) autophosphorylation, activation and recruitment of effectors to initiate a signaling cascade. (D) Mutations (*) in the extracellular sequence may promote the activation of the receptor without the presence of a ligand. The dashed box highlights a schematic diagram of extracellular ligand-binding domains (I and III) of EGFR. AKT, RAC serine/threonine-protein kinases; E2F1, transcription factor E2F1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinases; GRB2, growth factor receptor-bound protein 2; JAK, Janus kinase; MEK, MAP kinase kinases; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase-C2-α; PKC, protein kinase C; PLC, phospholipase C-γ-1; RAF, proto-oncogene c-RAF; RAS, GTPase-activating protein; SHC, SHC-transforming protein 1; SOS, son of sevenless homolog 1; STAT3, signal transducer and activator of transcription 3; I, II, III, IV, EGFR extracellular domains.