Cancer Therapies

Protein Kinases, their Inhibitors and Cancers

Protein kinases are one of the most important classes of human enzymes. These signaling molecules are involved in the protein phosphorylation process. Protein phosphorylation is crucial for maintaining and regulating normal cell growth, survival, and cell death.

Dysfunction in the protein kinase activity gives rise to an abnormal replication of cells (tumorigenesis). These cells can break away and spread to adjacent or distant sites (metastasis).

Genomic sequencing studies can map a complete set of genetic material (genome) from a cell. Defects in the genetic sequence is a marker of a particular disease, such as cancer.

Molecular biology scientists, using mass spectrometry techniques, have mapped the human genome, and identified over 500 protein kinases, most (478) of which belong to the classical protein kinase family and the rest being atypical protein kinases.

In addition, researchers have derived a large RNAi database that has identified essential protein kinases whose activity is required in cancer formation(genesis). These methods can identify the precise mutations occurring in the signaling pathway that are likely to contribute to the initiation and/or progression of cancer.

Identifying specific protein kinases is important to be able to create drugs that can lead to cancer cell death and control of cancers. Tyrosine, which is an amino acid, is the building block for a protein. Tyrosine Kinase Inhibitors (TKIs) is a class of targeted medicines that are used in many cancers.

The first protein kinase inhibition used for cancer therapy was Imatinib in 2001. The broad-spectrum imatinib was initially used to treat chronic myeloid leukemia (CML). Since then, it has been approved for several other cancers including gastro-intestinal stromal tumor(GIST), inoperable dermatofibrosarcoma, myelodysplasias and acute lymphoblastic leukemia.

Subsequently, Nilotinib (for imatinib-resistant CML), Sunitinib (for kidney cancer and as second-line therapy in the imatinib-resistant gastrointestinal cancer), Sorafenib (for kidney and liver cancers), Pazopanib and Everolimus (for advanced renal cancer, brain, and breast tumors) Vemurafenib, Vandetanib, Ruxolitinib, Crizotinib (for melanoma, thyroid and ALK-positive non-small cell lung cancer) etc. are being used.

Recently, Brigatinib and Osimertinib have shown promise as specific protein kinase inhibitors and many more drugs are undergoing clinical trials.

With such targeted medicines the cancer care has moved into a “personalized medicine domain”.

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