Tuesday, August 12, 2014

TARGETING CANCER

Targeting Therapy: Kinase Inhibitors



The human body functions on the backs of proteins called enzymes that modulate cellular behavior. These enzymes act as catalysts for a biochemical reaction within the human body milieu. One such class of enzymes called Kinases has a profound effect on the internal machinery of the cell. The human genome of 25,000 genes has a total of 500 kinase genes that have the ability to modify 30% of the genome.

With the advent of tumor genomics and high throughput machines the gene expression signatures has brought forth an array of medicines to counter malignancies.
Our understanding of the normal function of the kinases has enabled us to realize the pathology within. The governing gene of the kinases and their mutations, rearrangements and copy number variations can thus enhance, inhibit or modify the normal physiological function of the cell by interfering in the cellular signals and create chaos. It is this understanding and our ability to recognize that will help transform cancer care in the very near future.


A Kinase
acts as a mediator to transfer a phosphate moiety from the ATP molecule to a target substrate. A receptor recruited kinase most commonly such as EGFR is activated when the receptor plus ligand dimerizes the receptors and initiates the downstream cascade. The kinase phosphorylate other protein substrates to transduce the signal downstream via pathways directly or indirectly to the nucleus for enhancing proliferation or arresting growth. This act of phosphate transfer is called “phosphorylation.” Kinases have the ability to orient the substrate and the phosphate in such a manner so as to stabilize a high level energy reaction.
Courtesy McGraw Hill Companies

It is this activity that signals the interior of the cells to modify, grow, and self-destruct or cease-function. The kinases govern such initiation, inhibition or disruption of cellular activities, all through the charged phosphoryl-group. This regulatory function of the kinases comes from their ability to have reversible covalent modification of the substrates.
Courtesy McGraw Hill Companies

Such external modifying measures also create allosteric activity (feedback loops) within the interior of the cells that can potentiate and maximize the initial reaction.

Biotechnology companies are creating various Kinase Inhibitors. These inhibitors are used to suppress the kinase turned rouge -due to modification of its function as a forerunner of gene mutation. To prevent the mutated kinase from over-function and excessive uncontrolled cellular proliferation as happens in cancer, the inhibitors shut the signals emanating from the kinase and thus arrest any untoward cellular behavior.


There are a total of 60 Receptor Tyrosine Kinases (RTK) and an additional 30 intracellular Tyrosine Kinases that have been identified. Amongst the RTKs include the well-known families of: EGFR, PDGFR, VEGF, MET and ALK and amongst the non-RTKs included are: ABL, FES, FAK, SRC, IGFR and SCFR(c-kit) and JAK families. The various TKIs thus far developed include: Crizotinib (Xalkori), Dasatinib (Sprycel), Erlotinib (Tarceva), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Sorafenib (Nexavar), Sunitinib (Sutent). Most are familiar with Imatinib against the BCR-ABL mutation in CML, Crizotinib against the ALK mutated lung cancer and Sunitnib against renal cell carcinoma. The list of TKIs in development currently exceeds 38 at this time and future studies will highlight the benefits of these developments.

Aside from the RTKs there are three other kinases worth mentioning: Cycle Dependent kinases (CDKs), Phosphoinositol kinase (PIKs) and Mitogen Activated Protein Kinases (MAPKs).The CDK enzymes regulate the cell cycle in mitosis. CDKs control transcription, metabolism and because of their role in cell division they are vested heavily via mutation in creating malignancies within lymphatic tissue, pancreas and breast tissues. The PIKs phosphorylate the Inositol, which regulates the Insulin signaling pathways and is involved in both cancer and Insulin resistance. The MAPKs are activated by mitogens such as Epidermal growth factor (EGF), platelet derived growth factor (PDGF) and Insulin growth factor (IGF) to initiate a downstream signal transduction into the nucleus via the RAF-MEK-ERK pathway for cellular proliferation. Again kinase mutations cause dysregulation of the cell growth in most cases leading to cancer.

A word of caution
as we explore and enhance our understanding of the new TKIs is that the benefits from TKIs appear to be temporary in most cases.
The reasons are many-fold; the feedback loop mechanism within the cellular interior may abrogate the inhibitor function, cellular cross-talk between different pathways may take over the function of the kinase and cancer controlled degradation of the inhibitor might undermine the kinase inhibitor activity.
A case in point recently featured in the New England Journal of Medicine showed that a mutation of the Bruton Kinase in patients with Chronic Lymphocytic Leukemia (CLL) resulted in resistance to Ibrutinib a BTK inhibitor that is very effective in this disease!


The changing face of Cancer Care...Sustainability, Durability and the hope of longer term survival!

(Hey, I didn't say Science was easy, but it sure the heck beats contemplating the navel!)

References:

Manning G, Whyte DB. et al. (2002). "The protein kinase complement of the human genome". Science 298 (5600): 1912–1934

Higashiyama, Shigeki, Iwabuki, Hidehiko, Morimoto, Chie, Hieda, Miki, Inoue, Hirofumi, Matsushita, Natsuki (February 2008). "Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands". Cancer Science 99 (2): 214–20.

Stout TJ, Foster PG, Matthews DJ (2004).”High throughput structural biology in drug discovery: protein kinases.” Curr. Pharm. Des. 10 (10): 1069–82

Hunter T (1991). "Protein kinase classification". Meth. Enzymol. Methods in Enzymology 200: 3–37

Cantley, Lewis C (2012). "PI 3-kinase and disease". BMC Proceedings 6 (Suppl 3)

Canavese, Miriam; Santo, Loredana; Raje, Noopur (1 May 2012). "Cyclin dependent kinases in cancer: Potential for therapeutic intervention". Cancer Biology & Therapy 13(7): 451–457

Tony S. K. Mok Personalized medicine in lung cancer: what we need to know

Nature Reviews Clinical Oncology 8, 661-668 (November 2 2012).

Jennifer A. Woyach, M.D. et al. Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. N Engl J Med 2014; 370:2286-2294. June 12, 2014

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