hematology and oncology
Systemic Cancer Therapy
Targeted Therapies
Most targeted therapies are directed against tyrosine kinase–mediated cell signaling pathways. The best example are tyrosine kinase inhibitors, includingimatinib,dasatinib, andnilotinib, which are extremely effective in chronic myeloid leukemia. Many epithelial cancers have mutations that activate signaling pathways without the need for a receptor-ligand interaction, resulting in continuous proliferation of cancer cells. These mutated genes include those for growth factor receptors and the downstream proteins that transmit messages to the nucleus. Examples of such targeted therapies includeerlotinib,gefitinib, andosimertinib, which inhibit the epidermal growth factor receptor (EGFR) signaling pathway. These drugs are especially useful in lung cancer. Poly-adenosinediphosphate (ADP) ribose polymerase (PARP) inhibitors are used to treat ovary and hereditary breast cancers and includeolaparib,rucaparib,niraparib, and talaparib. Other examples include the nonspecific JAK1/2 inhibitorsruxolitinibandfedratinib, which are used to treat myeloproliferative neoplasms, andselinexor, which inhibits transport of proteins from the nucleus to cytoplasm, decreases cell proliferation, and is effective in multiple myeloma. A new direction in targeted cancer therapy is to use drugs that inhibit the gene product of a mutation independent of cancer type. Examples are drugs such asvemurafenib,dabrafenib, andencorafenib, which inhibit the protein produced by a mutation inBRAF. This mutation is common in melanoma but also occurs in some leukemias. Another example is drugs that inhibit abnormal proteins resulting fromMEKmutations, includingtrametinib,cobimetinib, andbinimetinib. 