Kinase Inhibitors

Background

Kinases (phosphotransferases) are a large family of enzymes involved in the transduction and amplification of signals on and in cells. They exert their effects by phosphorylating their substrates, that is, by adding a phosphate group to the molecules (Figure). Kinases have complicated names that are usually abbreviated: ALK, AXL, BCR-ABL, c-Kit, c-Met, ERBB, EGFR, FLT, HGFR, JAK, KIT, MET, mTOR, PDGFR, PI3, PKC, RAF, RET, ROCK, ROH, RON, SCF, SRC, TIE, TK, and VEGFR. It is now known that disruption in these pathways, for example uncontrolled activation of the kinases, can lead to cancer. For example, epidermal growth factor receptors (EGFs) are increased in lung cancer and breast cancer. Kinases are involved in tumor development, survival, vascularization and spread (metastasis). Mutations in the enzymes‘ coding genes represent a deeper cause of these disorders.

Effects

Kinase inhibitors (ATC L01XE) have cytostatic, antiproliferative, antitumor, and antiangiogenic properties. They bind and inhibit protein and lipid kinases in their function. As a result, for example, growth stimuli are no longer transmitted, the cancer cells are destroyed or the tumor is no longer supplied with sufficient blood and nutrients. Many kinase inhibitors are not selective and inhibit several of the enzymes. Consequently, and because the same kinases are involved in different cancers, the same agents can often be used in different diseases.

Indications

Today, most kinase inhibitors are used for cancer therapy. However, kinases are also involved in immunologic, neurologic, metabolic, and infectious diseases, among others, and other indications are approved in addition to various cancers. Indications include:

  • Lung cancer
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Chronic myeloid leukemia
  • Breast cancer
  • Thyroid cancer
  • Rheumatoid arthritis
  • Soft tissue sarcoma
  • Gastrointestinal tumors
  • Neuroendocrine tumors
  • Skin tumors, melanoma

Dosage

Most kinase inhibitors are now being developed so that they do not need to be administered as an infusion, but can be taken by patients themselves as a tablet or capsule.

Active ingredients (selection)

  • Alectinib (Alecensa)
  • Axitinib (Inlyta)
  • Cabozantinib (Cabometyx)
  • Crizotinib (Xalkori)
  • Lapatinib (Tyverb)
  • Lenvatinib (Lenvima)
  • Midostaurin (Rydapt)
  • Pazopanib (Votrient)
  • Regorafenib (Stivarga)
  • Sunitinib (Sutent)
  • Sorafenib (Nexavar)
  • Vandetanib (Caprelsa)

EGFR TKIs:

  • Afatinib (Gilotrif)
  • Erlotinib (Tarceva)
  • Gefitinib (Iressa)
  • Neratinib (Nerlynx)
  • Osimertinib (Tagrisso)

BCR-ABL inhibitors:

  • Bosutinib (Bosulif)
  • Imatinib (Gleevec)
  • Nilotinib (Tasigna)
  • Dasatinib (Sprycel)

Janus kinase inhibitors:

  • Baricitinib (Olumiant)
  • Ruxolitinib (Jakavi)
  • Tofacitinib (Xeljanz)
  • Upadacitinib (Rinvoq)

mTOR inhibitors:

  • Everolimus (Afinitor)
  • Sirolimus (= Rapamycin, Rapamune).
  • Temsirolimus (Torisel)

BRAF inhibitors:

  • Dabrafenib (Tafinlar)
  • Encorafenib (Braftovi)
  • Vemurafenib (Zelboraf)

MEK inhibitors:

BTK inhibitors:

CDK inhibitors:

  • Abemaciclib (Verzenios).
  • Palbociclib (Ibrance)
  • Ribociclib (Kisqali)

FLT3 inhibitors:

Veterinary drugs:

  • Toceranib (Palladia)

Some monoclonal antibodies can also be counted among the kinase inhibitors.

Adverse effects

Kinase inhibitors interfere somewhat selectively with cancer-initiating and -maintaining processes. Therefore, they tend to be better tolerated than traditional cytostatic drugs, which nonspecifically inhibit the proliferation of rapidly dividing cells. Nevertheless, like all drugs, kinase inhibitors are not free of side effects.One problem is the development of resistance of cancer cells to the active substances. Another disadvantage of the drugs is their high price – a monthly pack of the drugs often costs several thousand francs.