EGF receptor inhibitors

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 03.08.2022

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EGFR inhibitors; Inhibitors of the epidermal growth factor receptor; Signal Transduction Inhibitors

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EGF receptor inhibitors are receptor-blocking proteins that are used for the treatment of various EGFR-expressing tumors such as non-small cell lung cancer (NSCLC), breast cancer and colon cancer (see below).

General information: The humabe EGF receptor (HER) is a transmembrane receptor consisting of a glycoprotein belonging to the HER/ErbB family with 4 closely related receptor tyrosine kinases: GFR1/HER1 (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4) (Singh D et al. 2016). The EGF receptor is ubiquitously expressed in the body's tissues, including the keratinocytes of the basal epidermis and outer hair root sheath where it plays an important role in the epidermal barrier, antimicrobial defense and regulation of homeostasis. In the cell membrane of a healthy cell there are about 40,000-100,000 EGFR proteins.

Like all members of the HER/ErbB family, the human EGF receptor is located on the cell membrane, but its lower end projects into the cell interior (transmembrane receptor). Activation of the human EGF receptor is achieved by extracellular binding of various ligands of the EGF family (including Transforming Growth Factor-a (TGF-a), heparin-binding EGF, amphiregulin, betacellulin, epiregulin or neuregulin G2b).

After binding ligands to the extracellular receptor domain, the now activated tyrosine kinase of the EGF receptor directs the signal into the cell interior (signal transduction). ErbB receptors mediate their proliferative signals via a major cytoprotective signal transduction pathway involving adaptor proteins such as GRB2 and SHC, GTP exchange factors such as SOS, phospholipase Cγ (PLCγ), Ras, protein kinase C (PKC), Raf, MAPK, and PI-3 kinase-dependent signaling pathways. These signal transduction pathways directly or indirectly affect cell cycle control and transcriptional regulation, which trigger the biosynthetic machinery and cell proliferation. Furthermore, apoptosis is prevented.

An overexpression of the receptor is usually an indication of the transformation of a healthy cell into a tumor cell (Hossam M et al. 2016). For example, the number of EGF receptors is significantly increased in numerous tumors (up to 2 x106 receptors per cell). This overexpression is associated with a worse prognosis, lower survival rates and increased metastasis. Particularly affected are bronchial, breast, prostate, colon and ovarian cancers. In metastatic colorectal carcinomas, EGFR overexpression is over 80%. EGFR-expressing carcinomas are more resistant to chemotherapy.

Pharmacodynamics (Effect)
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In order to prevent receptor activation, two different approaches arise:

  • Inhibition of the binding of the ligands to the EGF receptor: This can be done, for example, by using a drug whose active ingredient has a similar structure to EGF, for example, to occupy the receptor in its place (receptor blockade).
  • Blocking the tyrosine kinase of the EGF receptor inside the cell: The EGF molecules can occupy the receptors, but the chemical reaction that triggers the cell division process is blocked. The mode of action of the most advanced compound among the EGFR inhibitors exploits these mechanisms of action.

Undesirable effects
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The use of EGFR inhibitors shows a variety of cutaneous side effects depending on the duration of therapy (Tischer B et al. 2017). Thus, follicular (acneiform) papulo-pustular exanthema develops in the area of the seborrheic zones in a period of 2 weeks. The lower trunk and extremities may also be affected. Comedones are typically absent. The severity of the exanthema is considered a measure of therapeutic response to EGFR inhibitors. EGF is thought to exert a control function on the inflammatory processes of acne vulgaris (Aydingoz IE et al. 2021).

It is not uncommon for patients to complain of xerosis of the skin and mucous membranes. Furthermore, painful paronychia and increased diffuse effluvium are observed. Trichomegaly, which may also affect the eyebrows and eyelashes, is conspicuous. Skin and hair changes usually regress spontaneously after therapy. However, depending on their severity, they can place considerable psychological strain on the patient and can therefore be therapy-limiting (Pfützner W 2018).

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Substances that have already been successfully tested and approved are:

  • Inhibitors of EGFR tyrosine kinase (tyrosine kinase inhibitors)
    • Afatinib (Giotrif®)non-small cell lung cancer (NSCLC), oral selective inhibitor of all growth-related members of the EGR family.
    • Dacomitinib (Vizimpro®) non-small cell lung cancer, EGFR mutation, first-line; approved in the EU as a film-coated tablet since 2019.
    • Gefitinib (Iressa®) non-small cell lung cancer with activating EGFR mutations.
    • Erlotinib (Tarceva®) non-small cell lung cancer, indication expansion for pancreatic cancer therapy
    • Lapatinib (Tyverb®) patients with breast cancer whose tumors overexpress HER2 (ErbB2).
    • Vandetanib (Caprelsa®) Thyroid neoplasms
  • EGFR-binding monoclonal antibodies
    • Cetuximab (Erbitux®) colorectal carcinoma)
    • Panitumumab (Vectibix®) advanced colorectal carcinoma (with KRAS wild-type)
    • Pertuzumab (Perjeta®) humanized monoclonal antibody that specifically binds to the extracellular dimerization domain (subdomain II) of the growth factor receptor protein HER2.
    • Necitumumab (Portrazza®) non-small cell lung cancer (NSCLC) with EGFR expression.
    • Trastuzumab (Herceptin®) advanced breast cancer
    • trastuzumab emtasine

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  1. Bayes M et al (2006) Gateways to clinical trials. Methods Find Exp Clin Pharmacol 28: 31-63
  2. Hossam M et al (2016) Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles. Arch Pharm (Weinheim). 349:573-593.
  3. Knight LA et al (2004) The in vitro effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours. BMC Cancer 23: 83
  4. Pfützner W (2018) Cutaneous drug reactions. In: Plewig G et al. (ed.) Braun-Falco`s Dermatology,Venerology and Allergology. Springer publishing house SS 559-624
  5. Saltz LB et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22: 1201-1208
  6. Singh D et al (2016) Review on EGFR Inhibitors: Critical Updates. Mini Rev Med Chem 16:1134-1166.
  7. Tischer B et al (2017) Dermatologic events from EGFR inhibitors: the issue of the missing patient voice. Support Care Cancer 25: 651-660.


Last updated on: 03.08.2022