Small-molecule inhibitors

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


BCR-ABL kinase inhibitors

A specific translocation between chromosomes 9 and 22 [Philadelphia chromosome, t(9;22)] fuses the BCR and ABL genes, producing a constitutively active tyrosine kinase that drives the uncontrolled proliferation of mature cells in chronic myeloid leukemia. Effective BCR-ABL kinase inhibitors include the following.

Imatinib (Gleevec)

  • Mechanism: binds and inhibits the tyrosine kinase activity of BCR-ABL kinase, the platelet-derived growth factor receptor, and c-kit
  • Route: oral
  • Uses: chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphocytic leukemia, gastrointestinal stromal tumor, dermatofibrosarcoma protuberans

Dasatinib (Sprycel)

  • Mechanism: binds to the BCR-ABL kinase at a separate location than imatinib and inhibits kinase activity, inhibits SRC kinase
  • Route: oral
  • Uses: chronic myeloid leukemia (especially imatinib-resistant disease), Philadelphia chromosome-positive acute lymphocytic leukemia
  • Notes: can cause pleural effusions and myelosuppression

Nilotinib (Tasigna)

  • Mechanism: binds and inhibits BCR-ABL kinase
  • Route: oral
  • Uses: chronic myeloid leukemia
  • Notes: can prolong the QT inter val. Contraindicated in patients with long QT syndrome, hypokalemia, or hypomagnesemia

Epidermal growth factor receptor inhibitors

the epidermal growth factor receptors (EGFRs) are a family of receptor tyrosine kinases that include EGFR/ErbB1, Her-2/ErbB2, Her-3/ErbB3, and Her-4/ErbB4, and these EGFRs are commonly overexpressed or overactive in solid tumors. When activated by soluble extracellular ligands, EGFRs initiate intracellular signaling cascades that can control various cell functions, such as promoting cell division and inhibiting apoptosis. Because of the similarity between the individual members of the EGFR family and their ability to form heterodimers, EGFR inhibitors are often able to target multiple different receptors. Available EGFR inhibitors include the following.

Erlotinib (Tarceva)

  • Mechanism: binds and inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR/ErbB1)
  • Route: oral
  • Uses: non-small– cell lung cancer (NSCLC), pancreatic cancer, squamous-cell head and neck cancer
  • Notes: associated with acneiform rash and diarrhea

Lapatinib (Tykerb)

  • Mechanism: reversible inhibitor of tyrosine kinase activity of the EFGR and the Her2/ErbB2 receptor
  • Route: oral
  • Uses: Her2-positive breast cancer
  • Notes: common side effects include diarrhea and palmar-plantar erythrodysesthesia ([PPe] hand-and-foot syndrome)

Vascular endothelial growth factor receptor inhibitors

The vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3) are receptor tyrosine kinases. When stimulated by soluble VEGF, these receptors initiate a signal transduction pathway critical for angiogenesis, the development of new blood vessels. Since tumors are dependent on the formation of new blood vessels for growth and survival, the VEGF pathway is an important therapeutic target. Active VEGF receptor inhibitors include the following.

Sorafenib (Nexavar)

  • Mechanism: inhibits vascular endothelial growth factor receptors (VEGFR-2, VEGFR-3), raf kinase, platelet-derived growth factor receptor β (PDGFR-β), and the KIT receptor tyrosine kinase (KIT)
  • Route: oral
  • Uses: renal cell carcinoma, hepatocellular carcinoma
  • Notes: common side effects include rash, diarrhea, and palmar-plantar erythrodysesthesia (hand-and-foot syndrome). It can lead to elevated Pt-INr in patients on warfarin.

Sunitinib (Sutent)

  • Mechanism: inhibits many receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), PDGFR-β, KIT, and the glial cell-line derived neurotrophic factor receptor (ret)
  • Route: oral
  • Uses: renal cell carcinoma, gastrointestinal stromal tumor
  • Notes: risk of decreased ejection fraction

Mammalian target of rapamycin inhibitors

Mammalian target of rapamycin (mTOR) is an intracellular protein kinase that serves as a nutrient sensor and can stimulate cell proliferation, and it may be overactive in malignant cells.

Temsirolimus (Torisel)

  • Mechanism: temsirolimus is metabolized to rapamycin, and both molecules bind to FKBP12 to inhibit the mammalian target of rapamycin (mTOR)
  • Route: intravenous
  • Uses: renal cell carcinoma
  • Notes: risk of hypersensitivity reaction, hyperglycemia, and rare risk of interstitial lung disease
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