Tyrosine kinase inhibitors

Tyrosine kinase inhibitors block signal transduction pathways in cells by inhibiting the tyrosine kinase activity of the intracellular receptor domain during signal transduction. This leads to a blockade of tumor cell growth.

Kinase-dependent signaling pathways are overactive in many proliferating tumor cells. Their growth can be slowed by inhibiting the kinases. Kinase inhibitors typically bind near the ATP-binding site of the kinase. They thus hinder ATP binding.

The kinases are predominantly tyrosine kinases, which is why these inhibitors are usually called tyrosine kinase inhibitors. However, some of these inhibitors also inhibit the threonine serine kinase in addition to the tyrosine kinase, so that they are also referred to as "multikinase inhibitors".

In many malignant tumors an unusually high number of growth factor receptors can be detected (e.g. EGFR = epidermal growth factor receptor, PDGFR, VEGFR, receptors for serine-threonine kinases). Regarding epidermal growth factor, 4 epidermal growth factor recept ors are known to date:

• HER1-HER4

Growth factors are partially produced by tumor cells themselves(autocrine loop). This leads to cells stimulating themselves to further cell divisions. For example, overexpression of HER1 occurs in most solid tumors. HER2 receptors (correspondingly, their inhibitors) play a significant role in the development and progression of breast carcinoma. They are located on the cell membrane. At one end, as with other receptor kinases, the tyrosine kinase protrudes into the cell interior. If the natural ligand, in this case EGF (see below growth factors), binds to its receptor domain on the outside of the cell, a complex chemical reaction (sigal cascade) is triggered inside the cell via the now activated tyrosine kinase, leading to cell proliferation and inhibition of apoptosis of the tumor cells.

Therefore, to stop this process, two different approaches arise:

Inhibition of the binding of the EGF molecule to the EGF receptor: This can be done, for example, by using a drug(monoclonal antibody) whose active ingredient has a similar structure to the EGF molecule to occupy the receptor in its place(receptor blockade). Examples listed for targeted monoclonal antibodies are:

• Cetuximab(Erbitux®): for colorectal carcinoma. Cetuximab competitively inhibits ligand binding and thus activation of the intracellular signaling cascade via binding to the extracellular domain of EGFR.

• Panitumumab (Vectibix®): EGFR-expressing, metastatic colon carcinoma (same mode of action as cetuximab).

Blocking the tyrosine kinase of the EGF receptor inside the cell: 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 agent among EGFR inhibitors exploits this mechanism of action.

Known tyrosine kinase inhibitors include:

• Imatinib (Gleevec®): inhibitory effect in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Possible other uses ( off-label use): dermatofibrosarcoma protuberans; systemic scleroderma; hypereosinophilia syndrome; mastocytosis; metastatic acrolentiginous malignant melanomas and mucosal melanomas in which C-Kit mutations are detected. Imatinib also inhibits the receptor PDGFR, which plays a role in myeloproliferative and myelodysplastic processes.
• Dasatinib (Sprycel®): orphan drug approved for chronic myeloid leukemia, primary eosinophilia when other therapies including imatinib are not tolerated, and acute lymphoblastic leukemia (ALL) in Philadelphia chromosome-positive adults (Ph+).
• Erlotinib (Tarceva®): inhibitory activity in non-small cell lung cancer (approved as second-line therapy since 2005). Erlotinib (approved together with gemcitabine for the treatment of pancreatic cancer since January 2007).
• Sorafenib (Nexavar®): inhibitory effect in hepatocellular carcinoma. There are also promising approaches for metastatic malignant melanoma, acute myeloid leukemia and myelodysplastic syndrome through preclinical studies.
• Gefitinib (Iressa®): EGFR tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (approved in several countries, including the USA).
• Vemurafenib (Zelboraf®): selective, oral inhibitor of the oncogene B-RAF, a serine/threonine kinase. B-RAF, a serine/threonine kinase is hyperactive in approximately 70% of malignant melanomas.
• Afatinib (Giotrif®): EGFR tyrosine kinase inhibitor (TKI)-naive adult patients with locally advanced and/or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations.

Side effects of therapies: EGF plays a major role in physiological processes of the skin. Under therapy with EGFR inhibitors (epidermal growth factor receptor inhibitors), various changes in skin and hair can occur. The HV usually occur 2-20 days after the start of therapy. These include skin dryness, itching, burning and possibly pain in the first 2 weeks, increased sensitivity to light, keratitis (inflammation of the cornea), fatigue syndrome, maculopapular or pustular rosacea-like exanthema (see Acne medicamentosa). The extent of the HV is generally regarded as a parameter for the response to therapy. According to the CTCAE-criteria (acronym for "Common Terminology Criteria for Adverse Events" or CTC = Common Toxicity Criteria) the acne-like exanthema is called "rash acneiform" and classified in 4 categories:

• Grade 1: Papules and/or pustules (< 10% of KO) with or without itching or pain
• Grade 2: Papules and/or pustules (10-30% of KO) with or without itching or pain,
• Grade 3: Papules and/or pustules (>30% of KO) with or without itching or pain, local superinfections; impairment of self-care.
• Grade 4: papules and/or pustules (regardless of the extent of the KO) with or without itching or pain, extensive superinfections; indication for intravenous antibiotic therapy; life-threatening condition.

Late complications are diffuse alopecia, changes in hair structure (wiry, dark hair), diffuse erythema (especially on the face), telangiectasia, hypertrichosis (face, increased growth of eyebrows and eyelashes), hand-foot syndrome, atrophy of the palmo-plantar skin, finger rhagades, paronychia.

There are no evidence-based recommendations for the treatment of acne-like exanthema associated with tyrosine kinase inhibitors!

A symptom-adapted treatment with hydrophilic creams or ointments without fragrances or other skin-irritating additives (no lotions or gels); if necessary, application of moist saline or black tea compresses. In case of late toxicity treatment depending on the symptoms.

The following rules of conduct also apply:

• Use mild bath or shower oils (e.g. Balneum Hermal or Balneum Hermal F)
• Avoid intensive sun (UV) radiation (no visits to solariums!).
• Consistent use of sun protection products (LF > 20).
• Avoid intensive skin contact with skin-irritating substances such as solvents, disinfectants, polishes, etc.
• Avoidance of strong physical skin stress such as wearing shoes that are too tight, carrying heavy luggage, hot blow-drying of hair, intensive rubbing down of the skin, wet shaving (micro-trauma).

1. Gutzmer R et al (2011) Management of cutaneous adverse effects of EGFR inhibitors: Recommendations of a German expert panel for the primary care physician. JDDG 9:195-203
2. Kähler HC et al. (2009) Skin changes caused by "targeted therapies" in oncological patients. Dermatologist 60: 433-440
3. Potthoff K et al (2010) Therapy and prophylaxis of EGFR inhibitor-induced skin reactions. Drug therapy 28: 191-198
4. Wozel G et al (2010) Undesirable dermatological effects in therapeutic inhibition of the VEGF pathway. JDDG 8: 243-249

5. Yang J CH et al (2013): Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations. Journal of Clinical Oncology 31:3342-3350