Table 1.
Resistance mechanisms to chemotherapy (left), cetuximab (middle) and immunotherapy (right), described in head and neck squamous cell carcinoma.
| CHEMOTHERAPY | CETUXIMAB | |||
|---|---|---|---|---|
| Target alterations | DNA damage | EGFR and its ligands | EGFR alterations | |
| Loss of PTPRS | ||||
| EGFR variant III | ||||
| Nuclear translocation | ||||
| SNP EGFR-K521 | ||||
| DNA damage response effectors | EGFR G465R and concurrent EGFR G33S and EGFR N56K | |||
| ERCC1 expression | Competition with other ligands | |||
| ATR, WEE1 and PARP activation | Aberrant expression of TGF-a, TGF-b, EGF, HB-EGF, amphiregulin and heregulin | |||
| EGFR downstream effectors | STAT3 activation by EGFR, JAK2 or a Src Kinase | |||
| Src kinase activation | ||||
| RAS/MAPK pathway activation | ||||
| PI3K/Akt/mTOR pathway activation (e.g. PTEN mutation) | ||||
| Bypass pathway activation | Apoptosis evasion | Survivin expression | RTK activation | MET, AXL, HER2, HER3, ROR2, IGF-1R and VEGFR |
| Increased XIAP and TRAIL expression | Apoptosis evasion | Loss of the tumor suppressor gene TP53 | ||
| Metabolism | Hypoxia (i.e. HIF-1α overexpression) | |||
| Epithelial-to-mesenchymal transition / cancer stem cells | NEDD4 overexpression | Expression of lymphotoxin | ||
| miR-139-5p down-regulation | EGFR methylation | |||
| IL-6/STAT3 pathway activation | Secretion of CTX-containing extracellular vesicles | |||
| Increased expression of CD44 and Oct-4 | Upregulation of EMT-related genes | |||
| Upregulation of ABC transporter genes | Loss of the tumor suppressor gene SMAD4 | |||
| Increased ALDH1 expression | ||||
| Epigenetic modifications | Activation of miR-302 | Altered expression of growth factor receptors and EMT-related genes by: | ||
| Increased FOXD2-AS1 expression | DNA methylation | |||
| Up-regulation of histone methyltransferase DOT1L | Histone modifications | |||
| NEFL promoter hypermethylation | Chromatin remodeling | |||
| Elevated expression of PAK2 | Noncoding RNAs | |||
| miR-629-3p expression | ||||
| TME | Enhanced expression of miR-96-5p | |||
| ALK1 activation | T regs and MDSC proliferation | |||
| SDF-1/CXCR4 expression | T cells exhaustion or impairment | |||
| Cancer associated fibroblasts (CAF) proliferation | Toll-like receptor 4 (TLR4) pathway activation | |||
| Cancer associated fibroblasts (CAF) proliferation | ||||
| IMMUNOTHERAPY | |
|---|---|
| Intrinsic resistance | Tumor Immunogenicity and Antigen presentation |
| Selection of subclones lacking the expression of neoantigens | |
| downregulation of MHC class I (MHC-I) | |
| Loss of function of β2-microglobulin | |
| Alterations in STAT1 | |
| Oncogenic pathways | |
| MAPK pathway | |
| WNT/β-catenin pathway | |
| PI3K pathway | |
| Soluble molecules | |
| Secretion of pro-tumoral cytokines IL-6, and IL-10 | |
| IDO1 overexpression | |
| Secretion of immunosuppressive exosomes containing TGF-β, PD-1 and CTLA4 | |
| Extrinsic resistance | Inhibitory checkpoint molecules |
| CTLA-4 expression in Treg TILs | |
| LAG-3 | |
| TIM-3 | |
| KIR2DL-1, KIR2D-2, KIR2D-3 | |
| Stimulatory agonist molecules | |
| Costimulatory agonists: Ox40, 4-1BB, ICOS and CD40 | |
| Immunosuppressive cells | |
| Myeloid derived suppressor cells | |
| Tregs | |
| Tumor-associated macrophages | |
For each resistance mechanism, preclinical and/or clinical evidence of their role in resistance as well as combined therapeutic strategies to overcome it are developed in the manuscript.