Introduction of EGFR
EGFR is the expression product of proto-oncogene C-ERBB1, the receptor of EGF cell proliferation and signal transduction. It is a member of epidermal growth factor receptor (HER) family, which includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3)，and HER4 (erbB4). Mutation or over-expression of EGFR usually leads to tumorigenesis. EGFR gene is located on the short arm of chromosome 7, EGFR is a glycoprotein, belongs to tyrosine kinase type receptor, a membrane through, molecular weight 170KDa.
EGFR Signal Pathway
The EGFR protein is a transmembrane protein, an extracellular EGFR monomer without the activity of ammonia kinase, which binds to the ligand. In the absence of a ligand, the EGFR monomer on the surface of the cell membrane is continuously ingested into the cell. When there is an excess of EGFR monomer, two EGFR monomers will polymerize into a dimer without ligand. And this EGFR dimer activates itself and further activates downstream cellular signaling pathways. In the presence of ligands, two EGFR monomers with ligands combine to form a kinase-active dimer, and the dimer phosphokinase phosphorylates the EGFR dimer itself. Phosphorylated residues are binding sites that recruit adaptors and additional tyrosine kinase substrates to enhance tyrosine kinase activity, phosphorylate proteins in downstream signaling pathways, and activate downstream signaling pathways. Including MAPK, Akt and JNK pathway, induced cell proliferation. EGFR may also polymerize with other members of the ErbB receptor family (ErbB2/Her2/neu) to activate it.
The tyrosine kinase active site of EGFR is mainly located between exon 18 and exon 24, such as deletion mutation of EGFR exon 19 and L858R mutation, which leads to the change of amino acid residue 858 from Leucine to Arginine. As a result, the two monomers of EGFR bind directly in the absence of ligands, forming a self-activating dimer that continuously activates tyrosine kinase activity. There are two main signal transduction pathways downstream of EGFR: one is Ras/ Raf/MEK/ERK-MAPK pathway, the other is PI3K/Akt/mTOR pathway. The gene mutation of the key genes K-Ras, BRAF, PIK3CA downstream of the EGFR signal transduction system, and the inactivation of the tumor suppressor gene PTEN are the focus of drug research.
EGFR and Disease
EGFR-TKIs (Epidermal growth factor receptor tyrosine kinase inhibitors) is widely used in advanced non-small cell lung cancer (non-small cell lung cancer, NSCLC), especially in patients with lung adenocarcinoma with epidermal growth factor receptor EGFR gene mutation. On the one hand, macromolecular targeted drugs specifically recognize the antibody of EGFR-ligand binding site in the extracellular domain, and block the binding of the ligand to EGFR by competing with the ligand for EGFR to block the ligand-induced activation of EGFR. On the other hand, the amount of EGFR on the cell surface was decreased by inducing the endocytosis of EGFR. Small molecule targeted drugs inhibit the activation of downstream biological signaling pathways by competing with ATP for the tyrosine kinase active site of EGFR.
Targeted drugs targeting EGFR approved by FDA
| Drug Name | Trade Name | Indication | Listing Date |
| Gefitinib | Iressa | metastatic non-small cell lung cancer with deletion of exon 19 or mutation of exon 21 of the EGFR gene | 2003 |
| Erlotinib | Tarceva | First-line treatment of metastatic non-small Cell Lung Cancer with deletion of Exon 19 or mutation of Exon 21 of EGFR Gene | 2004 |
| Cetuximab | Erbitux | Combined radiotherapy for local or regional advanced squamous cell carcinoma of head and neck, chemotherapy based on 5-fluorouracil and platinum for locally recurrent or metastatic squamous cell carcinoma of head and neck | 2004 |
| Panitumumab | Vectibix | Treatment of metastatic Colorectal Cancer with KRAS Wild-type (mCRC) | 2006 |
| Icotinib | Kemena | First-line treatment of locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutation (NSCLC) | 2011 |
| Nimotuzumab | taxinson | Combined radiotherapy for stage Ⅲ / Ⅳ nasopharyngeal carcinoma with EGFR expression | 2012 |
| Afatinib | Gilotrif | FDA-approved first-line treatment for metastatic non-small Cell Lung Cancer with deletion of Exon 19 or substitution mutation of Exon 21 of the EGFR Gene | 2013 |
| Osimertinib | Tagrisso | Treatment of non-small cell lung cancer with EGFR T790M mutation | 2015 |
| Necitumumab | Portrazza | Combination of gemcitabine and cisplatin in the treatment of metastatic squamous cell lung cancer | 2015 |
| Olmutinib | Olita | Treatment of non-small cell lung cancer with EGFR T790M mutation approved by South Korea for locally advanced or metastatic non-small cell lung cancer previously treated with EGFR TKI | 2016 |
| Phase | Code Name (CD) | Drug Name (CD, GN, BN) | Organization | Condition |
| Phase I | AG-1517; PD-153035; SU-5271; WHI-P79; ZM-252868 | AG-1517; PD-153035; SU-5271; WHI-P79; ZM-252868 | Pfizer (Originator); Sugen (Originator); | Psoriasis; Cancer |
| Phase I | BIBX-1382; BIBX-1382BS | BIBX-1382; BIBX-1382BS, Falnidamol (Rec INN) | Boehringer Ingelheim (Originator); | Cancer |
| Phase I | P-54-FP | P-54-FP | Medical Research Council (MRC) (Originator); | Cancer |
| Phase I | AV-412; MP-412 | AV-412; MP-412 | Mitsubishi Tanabe Pharma (Originator); AVEO Pharma; | Cancer, solid tumor; Cancer |
| Phase I | AC-480; BMS-599626 (former code) | AC-480; BMS-599626 (former code) | Bristol-Myers Squibb (Originator); Daiichi Sankyo; | Cancer, solid tumor; Glioma |
| Phase I | JNJ-26483327 | JNJ-26483327 | Johnson & Johnson (Originator); | Cancer, solid tumor |
| Phase I | 806; Antibody 806; ch806; mAb806 | 806; Antibody 806; ch806; mAb806 | Ludwig Institute for Cancer Research (Originator); Abbott; Life Science Pharmaceuticals; | Cancer, solid tumor; Cancer |
| Phase I | AT-13387A; AT-13387AU; 66226JUH2I (UNII code); AT-13387 (free base) | AT-13387A; AT-13387AU; 66226JUH2I (UNII code); AT-13387 (free base), Onalespib lactate (USAN; Rec INN) | Astex Pharmaceuticals (Originator); National Cancer Institute; | Cancer, head and neck (squamous cell carcinoma); Cancer, breast; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC); Melanoma; Gastrointestinal stromal tumor (GIST) |
| Phase I | D2C7-(scdsFv)-PE38 KDEL; D2C7-IT; scds-D2C7-PE38KDEL | D2C7-(scdsFv)-PE38 KDEL; D2C7-IT; scds-D2C7-PE38KDEL | Duke University (Originator); US Department of Health & Human Services (Originator); | Carcinoma, squamous cell; Glioblastoma multiforme |
| Phase I | AL-6802; SIM-6802 | AL-6802; SIM-6802, Simotinib hydrochloride | Advenchen Laboratories (Originator); Simcere Pharmaceutical; | Cancer, lung (non-small cell) (NSCLC); Cancer |
| Phase I | EGFR-ECD/VSSP/MONT | EGFR-ECD/VSSP/MONT | Centro de Inmunologia Molecular (CIM) (Originator); | Cancer, prostate |
| Phase I | 11C-PD-153035; [11C]PD-153035; [Methoxy-11C]PD-153035 | 11C-PD-153035; [11C]PD-153035; [Methoxy-11C]PD-153035 | Karolinska Institutet (KI) (Originator); Shandong Tumor Hospital; | Cancer, lung (non-small cell) (NSCLC); Cancer |
| Phase I | AVL-292; CC-292; DRU6NG543J (UNII code) | AVL-292; CC-292; DRU6NG543J (UNII code), Spebrutinib (USAN; Rec INN) | Celgene (Originator); | Lymphoma, diffuse large B-cell; Lymphoma, follicular; Rheumatoid arthritis; Lymphoma, B-cell; Autoimmune disease; Small lymphocytic lymphoma; Leukemia, chronic lymphocytic |
| Phase I | HKI-357; PB-357; PF-5208766; WAY-178357 | HKI-357; PB-357; PF-5208766; WAY-178357 | Pfizer (Originator); Puma Biotechnology; | Cancer |
| Phase I | QLNC-120; 6Q2E32HVE7 (UNII code) | QLNC-120; 6Q2E32HVE7 (UNII code), Selatinib ditosilate | Qilu Pharmaceutical (Originator); | Cancer, breast |
| Phase I | DBPR-112 | DBPR-112 | National Health Research Institutes (Originator); | Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC) |
| Phase I | 18F-Fluoro-PEG6-IQPA; [18F]F-PEG6-IPQA | 18F-Fluoro-PEG6-IQPA; [18F]F-PEG6-IPQA | Kanazawa University (Originator); M.D. Anderson Cancer Center (Originator); | Diagnostics; Cancer, lung |
| Phase I/II | AEE-788; NVP-AEE-788 | AEE-788; NVP-AEE-788 | Novartis (Originator); | Glioblastoma multiforme; Cancer, solid tumor; Cancer, colorectal metastatic |
| Phase I/II | MDX-214 | MDX-214 | Bristol-Myers Squibb (Originator); | Cancer, solid tumor; Immunological Disorders |
| Phase I/II | INCB-007839; INCB-7839 | INCB-007839; INCB-7839, Aderbasib (Prop INN; USAN) | University of Minnesota; Incyte (Originator); | Cancer, breast; Cancer, solid tumor; Lymphoma, non-Hodgkin |
| Phase I/II | HMPL-813 | HMPL-813, Epitinib succinate | Hutchison China MediTech (Chi-Med) (Originator); | Glioblastoma multiforme; Cancer, solid tumor |
| Phase I/II | CEP-32496; RXDX-105 | CEP-32496; RXDX-105, Agerafenib hydrochloride (Prop INNM) | Roche; Teva (Originator); Daiichi Sankyo (Originator); | Cancer |
| Phase I/II | S-222611; 60OIK33ZQR (UNII code) | S-222611; 60OIK33ZQR (UNII code), Epertinib (Rec INN) | Shionogi (Originator); | Cancer, breast metastatic; Cancer, solid tumor |
| Phase II | BIO-300; G-2535; PTI-G4660; SIPI-9764-I | BIO-300; G-2535; PTI-G4660; SIPI-9764-I, 4′,5,7-Trihydroxyisoflavone; Genistein, Bonistein | National Cancer Institute; Bausch & Lomb; Astellas Pharma; Humanetics; National Institutes of Health; US Army Med Res Inst of Chemical Defense; Uniformed Services University; Universita degli Studi di Messina; SurModics; | Renal failure, chronic; Fibrosis, cystic; Cancer, bladder; Cancer, breast; Cancer, prostate; Melanoma, metastatic; Eye Disorders; Poisoning; Cancer, lung (non-small cell) (NSCLC); Erectile dysfunction; Cancer, endometrium; Cancer, kidney (renal cell carcinoma, clear cell); Fibroids, uterine (myoma); Infection, HIV; Osteopenia; Endometrial hyperplasia; Acute radiation syndrome |
| Phase II | IdB-1056 | IdB-1056, Delphinidin; Delphinidin chloride; Delphinidol; Ephdine | Indena; | Other cardiovascular disorders; Cancer |
| Phase II | VK3 | VK3, Menadione (Rec INNM; BAN; USAN); Vitamin K3, Kappaxin; Thyloquinone | Albert Einstein College of Medicine; Sanofi (Originator); Bristol-Myers Squibb (Originator); Talon Therapeutics; Lilly (Originator); | Hemorrhage; Cancer |
| Phase II | CI-1033; PD-183805 (free base) | CI-1033; PD-183805 (free base), Canertinib dihydrochloride (Rec INNM; USAN) | Pfizer (Originator); | Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC) |
| Phase II | CP-547632; OSI-632 | CP-547632; OSI-632 | Pfizer (Originator); Astellas Pharma (Originator); | Cancer, lung (non-small cell) (NSCLC); Cancer, ovary |
| Phase II | EKB-569; WAY-EKB-569 | EKB-569; WAY-EKB-569, Pelitinib (USAN; Rec INN) | National Cancer Institute; Pfizer (Originator); | Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, mouth; Cancer, colorectal |
| Phase II | TP-38 | TP-38, Cervene | Duke University (Originator); Teva; | Glioblastoma multiforme; Cancer, brain |
| Phase II | EXEL-7647; KD-019; KD-020; XL-647; F6XM2TN5A1 (UNII code) | EXEL-7647; KD-019; KD-020; XL-647; F6XM2TN5A1 (UNII code), Tesevatinib (USAN; Rec INN) | Symphony Evolution; Kadmon; Exelixis (Originator); | Cancer, metastatic; Glioblastoma; Cancer, lung (non-small cell) (NSCLC); Cancer, metastatic (to brain); Polycystic kidney, autosomal dominant; Polycystic kidney, autosomal recessive |
| Phase II | 823296; GW-823296 | 823296; GW-823296, Orvepitant (USAN; Rec INN) | GlaxoSmithKline (Originator); NeRRe Therapeutics; | Anxiety disorder; Depression; Cough, chronic; Stress, post-traumatic; Pruritus |
| Phase II | AZD-8931 | AZD-8931, Sapitinib (Rec INN) | AstraZeneca (Originator); | Cancer, gastrointestinal; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal |
| Phase II | Anti-EGFR ILs-DOX; C225-ILS-DOX | Anti-EGFR ILs-DOX; C225-ILS-DOX | Universitaetsspitals Basel (USB) (Originator); SAKK; | Glioblastoma multiforme; Cancer, breast; Cancer, solid tumor |
| Phase II | BMS-690514 | BMS-690514 | Bristol-Myers Squibb (Originator); | Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor |
| Phase II | ARQ-197 | ARQ-197, Tivantinib (Prop INN; USAN) | National Cancer Institute; Istituto Oncologico Veneto; ArQule (Originator); Kyowa Hakko Kirin; Dana-Farber Cancer Institute; Daiichi Sankyo; | Cancer, breast metastatic; Cancer, pancreas; Cancer, liver (hepatocellular carcinoma); Cancer, lung (small cell) (SCLC); Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal metastatic; Mesothelioma, malignant; Cancer, stomach; Cancer, kidney metastatic; Cancer, germ cells; Cancer, prostate metastatic |
| Phase II | GT-MAb 2.5-GEX | GT-MAb 2.5-GEX, Gatipotuzumab (Rec INN), PankoMab; PankoMab-GEX | Glycotope (Originator); | Cancer, ovary (epithelial); Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal; Cancer, fallopian tube; Cancer, peritoneum |
| Phase II | GA-201; R-7160; RG-7160; RO-5083945 | GA-201; R-7160; RG-7160; RO-5083945, Imgatuzumab (USAN; Rec INN) | Roche (Originator); | Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC); Lymphoma; Cancer, solid tumor; Cancer, colorectal |
| Phase II | BIBW-2948; BIBW-2948 BS | BIBW-2948; BIBW-2948 BS | Boehringer Ingelheim (Originator); | Chronic obstructive pulmonary disease (COPD) |
| Phase II | Sym-004 | Sym-004, Futuximab/modotuximab (Rec INN) | Symphogen (Originator); | Cancer, head and neck (squamous cell carcinoma); Gliosarcoma; Glioblastoma multiforme; Cancer, lung (non-small cell) (NSCLC) (squamous cell carcinoma); Esophageal carcinoma (squamous cell); Cancer, colorectal |
| Phase II | HM-781-36; HM-781-36B; NOV-1201; NOV-120101 | HM-781-36; HM-781-36B; NOV-1201; NOV-120101, Poziotinib (Rec INN) | Spectrum Pharmaceuticals; Luye Pharma; Hanmi (Originator); | Cancer, breast metastatic; Cancer, lung (non-small cell) (NSCLC) (adenocarcinoma); Cancer, breast; Cancer, lung; Cancer, head and neck; Cancer, stomach |
| Phase II | GT-MAb 5.2-GEX | GT-MAb 5.2-GEX, Tomuzotuximab (Rec INN), CetuGEX | Glycotope (Originator); | Female reproductive system cancer; Cancer, head and neck (squamous cell carcinoma); Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal |
| Phase II | DL11f; MEHD-7945A; RG-7597 | DL11f; MEHD-7945A; RG-7597, Duligotumab (Rec INN); Duligotuzumab (Prop INN; USAN) | Genentech (Originator); | Cancer, head and neck (squamous cell carcinoma); Cancer, solid tumor; Cancer, colorectal metastatic |
| Phase II | BB-401; pNGVL1-U6-EGFR-AS; pNGVL1-U6-EGFRAS | BB-401; pNGVL1-U6-EGFR-AS; pNGVL1-U6-EGFRAS | NantWorks; University of Pittsburgh (Originator); Benitec Biopharma; | Cancer, head and neck (squamous cell carcinoma) |
| Phase II | ABT-806; W984C353CG (UNII code) | ABT-806; W984C353CG (UNII code), Depatuxizumab (Rec INNM; Rec INN) | Ludwig Institute for Cancer Research (Originator); Life Science Pharmaceuticals; AbbVie; | Cancer, gastrointestinal; Cancer, solid tumor; Glioma |
| Phase II | PYM | PYM, Bleomycetin; Bleomycin A5 hydrochloride; Pingyangmycin; Zhengguangmycin A5 | Beijing Stomatol Hosp Capital Med Univ; Chinese Academy of Medical Sciences; Shanghai Jiao Tong University; Affiliated Hospital Xuzhou Medical Coll; Nanfang Hospital Southern Medical Univ; | Malformation, vascular; Cancer, cervix; Cancer, mouth (squamous cell); Hemangioma, hepatic; Cancer, esophagus |
| Phase II | BI-836845 | BI-836845, Xentuzumab | MorphoSys; Boehringer Ingelheim (Originator); | Cancer, breast; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC) |
| Phase II/III | AR-00334543; ARRY-334543; ARRY-543; ASLAN-001; QBT-01; SPS-4370 | AR-00334543; ARRY-334543; ARRY-543; ASLAN-001; QBT-01; SPS-4370, Varlitinib tosylate (Prop INNM; USAN) | Array BioPharma (Originator); ASLAN Pharmaceuticals; Hyundai Pharm; | Cancer, breast metastatic; Cancer, pancreas; Cholangiocarcinoma; Cancer, biliary; Cancer, liver (hepatocellular carcinoma); Cancer, solid tumor; Cancer, gastroesophageal junction; Cancer, stomach |
| Phase III | CHIR-258; CHIR-258 lactate; CHIR-258LC; GFKI-258; NVP-TKI258; TKI-258 | CHIR-258; CHIR-258 lactate; CHIR-258LC; GFKI-258; NVP-TKI258; TKI-258, Dovitinib lactate (USAN) | Novartis (Originator); Samsung Medical Center; Oncology Venture; | Cancer, breast metastatic; Cancer, pancreas; Leukemia, acute myeloid; Cancer, head and neck (adenoid cystic carcinoma); Endocrine cancer; Glioblastoma multiforme; Cancer, liver (hepatocellular carcinoma); Multiple myeloma; Cancer, prostate (castration-resistant); Cancer, lung (non-small cell) (NSCLC); Cancer, endometrium; Cancer, kidney (renal cell carcinoma); Cancer, stomach; Melanoma; Gastrointestinal stromal tumor (GIST); Cancer, colorectal; Mesothelioma, pleural; Von Hippel-Lindau disease; Pheochromocytoma; Cancer, bladder (urothelial carcinoma); Cancer, salivary glands (adenoid cystic carcinoma) |
| Phase III | 2F8 | 2F8, Zalutumumab (Prop INN; USAN), HuMax-EGFr | Bristol-Myers Squibb (Originator); Genmab; | Cancer, head and neck (squamous cell carcinoma); Cancer, lung (non-small cell) (NSCLC); Cancer, head and neck; Cancer, colorectal |
| Phase III | ASP-7487; OSI-906; OSI-906AA | ASP-7487; OSI-906; OSI-906AA, Linsitinib (Prop INN; USAN) | National Cancer Institute; Multiple Myeloma Research Foundation; Astellas Pharma (Originator); Vanderbilt University; University of Colorado; | Cancer, breast metastatic; Sarcoma, Ewing; Cancer, liver (hepatocellular carcinoma); Multiple myeloma; Cancer, lung (non-small cell) (NSCLC); Gastrointestinal stromal tumor (GIST); Cancer, colorectal; Cancer, ovary (epithelial recurrent); Cancer, prostate metastatic; Carcinoma, adrenocortical |
Conclusion
The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). There is evidence that cooperation between multiple ErbB receptors and homologs is necessary to induce cell transformation. In particular, the growth and survival of cancer cells appear to be maintained by the receptor/ligand network of the ErbB family. This phenomenon is also important for treatment because the response of anti-EGFR drugs may depend on the overall level of expression of ErbB receptors and ligands in tumor cells.
References
1. Normanno, N., De Luca, A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R., … & Salomon, D. S. (2006). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366(1), 2-16.
2. Blobel, C. P. (2005). ADAMs: key components in EGFR signalling and development. Nature reviews Molecular cell biology, 6(1), 32.
3. Soria, J. C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., … & Okamoto, I. (2018). Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. New England journal of medicine, 378(2), 113-125.
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