Table 1.
Potential important alterations in ADC and SCC
| Gene | Status (M, C or F)* | Frequency (%) | Available GEMMs | Currently available targeted therapies | Selected potential targeted therapies | Refs | ||
|---|---|---|---|---|---|---|---|---|
| ADC | SCC | Preclinical evidence | Clinical evidence | |||||
| Receptor tyrosine kinases | ||||||||
| EGFR | M or C | 10 (M) | 2–3 | L858R, Del19, T790M and Ins20 | Erlotinib, gefitinib and afatinib | AZD9291, CO-1686 and HM61713 | 126 | 11 |
| FGFR1 | C | N/A | 20 | N/A | N/A | Dovitinib, ponatinib, AZD4547 and BGJ398 | 150 | 22 |
| FGFR2 | M or C | 3 (M) | 3 | N/A | N/A | Dovitinib, ponatinib, AZD4547 and BGJ398 | 151 | 20 |
| ALK | F | 3–5 | <1 | ALK fusion, L1196M and F1174L | Crizotinib and ceritinib | AP26113, alectinib, ganetespib and PF-06463922 | 125 | 18 |
| MET | C | 2–4 | N/A | Overexpression | Crizotinib | Tivantinib, cabozantinib, INC280 and onartuzumab | 152 | 14 |
| ROS1 | F | 1–2 | N/A | N/A | Crizotinib | PF-06463922 | 153 | 17 |
| NTRK1 | F | 1–2 | N/A | N/A | N/A | Crizotinib and lestaurtinib | 21 | 21 |
| RET | F | 1 | N/A | N/A | N/A | Carbozantinib and vandetanib | 154 | 16 |
| HER2 | M or C | 2–4 (M) | N/A | HER2-YVMA insertion | N/A | Neratinib, afatinib, lapatinib and trastuzumab | 155 | 19 |
| DDR2 | M | N/A | 2–3 | N/A | N/A | Dasatinib | 27 | 27 |
| PDGFRA | M | 6–7 | 4 | N/A | N/A | Sunitinib | 156 | 28 |
| Signalling | ||||||||
| KRAS | M | 15–25 | 1–2 | G12D, G12C and G12V | N/A | Selumetinib plus docetaxel combination | 157 | 158 |
| NF1 | M | 12 | 10 | Null | N/A | 159 | 28 | |
| BRAF | M | 1–6 | 4–5 | V600E | N/A | Vemurafenib, dabrafenib and trametinib | N/A | 160 |
| PIK3CA | M | 5 | 15 | p110α | N/A | BEZ235, BKM120 and GDC0941 | 99 | 161 |
| MEK1 | M | 1 | N/A | N/A | N/A | Selumetinib and trametinib | N/A | 162 |
| NOTCH1 | M | 8 | 1 | Conditional null | N/A | N/A | 163 | 164 |
| Epigenetic factors | ||||||||
| MLL2 | M | 9 | 20 | N/A | N/A | N/A | 165 | 28 |
| EZH2 | M | 2 | 2 | N/A | N/A | N/A | 166 | 28 |
| TET2 | M | 3 | 2 | N/A | N/A | N/A | 167 | 28 |
| DNMT3A | M | 4 | 1 | N/A | N/A | N/A | 168 | 28 |
| Transcription factors | ||||||||
| SOX2 | C | 6 | 65 | Overexpression | N/A | N/A | 7 | 103 |
| MYC | C | 25 | N/A | Overexpression | N/A | N/A | 133 | 104 |
| Proteolysis | ||||||||
| KEAP1 | M | 17 | 12 | N/A | N/A | N/A | 169 | 170 |
| Cell cycle | ||||||||
| CDKN2A | M | 7 | 15 | Null | N/A | N/A | 171 | 172 |
| Ligand | ||||||||
| NRG1 | F | <1 | N/A | N/A | N/A | N/A | 15 | 15 |
| Tumour suppressor | ||||||||
| TP53 | M | 52 | 79 | Conditional null and R172H | N/A | N/A | 98 | 173 |
| LKB1 | M | 9 | 2 | Conditional null | N/A | N/A | 65 | 174 |
| PTEN | M | 2 | 8 | Conditional null | N/A | BEZ235, BKM120 and GDC0941 | 175 | 176 |
ADC, adenocarcinoma; ALK, anaplastic lymphoma kinase; CDKN2A, cyclin-dependent kinase inhibitor 2A (which encodes INK4A and ARF); DDR2, discoidin domain-containing receptor 2; Del19, EGFR exon 19 deletion; DNMT3A, DNA (cytosine-5-)-methyltransferase 3α; EGFR, epidermal growth factor receptor; EZH2, enhancer of zeste homologue 2; FGFR1, fibroblast growth factor receptor 1; GEMM, genetically engineered mouse model; Ins20, EGFR exon 20 insertion; KEAP1, kelch-like ECH-associated protein 1; LKB1, liver kinase B1; MLL2, mixed-lineage leukaemia 2; N/A, not available; NF1, neurofibromin 1; NRG1, neuregulin 1; NTRK1, neurotrophic tyrosine kinase, receptor, type 1; PDGFRA, platelet-derived growth factor receptor-α; PIK3CA, PI3K catalytic subunit-α; SCC, squamous cell carcinoma; SOX2, SRY-box 2; TET2, TET methylcytosine dioxygenase 2.
Status refers to mechanisms by which each gene is altered in tumours — mutation (M), copy number gain (C) or fusion (F).