Oncogene addiction and synthetic lethality: keys to discovery of new anticancer drugs. Panel A. Normal cells receive environmental signals that activate signaling pathways (pathways A, B, and C) that together promote G1 to S phase transition and passage through the cell cycle. Inhibition of one pathway (such as pathway A by a targeted inhibitor) has no significant effect due to redundancy provided by pathways B and C. In cancer cells, oncogenic mutations lead over time to dependency on the activated pathway, with loss of significant input from pathways B and C. The dependency or addiction of the cancer cell to pathway A makes it highly vulnerable to inhibitors that target components of this pathway. Clinically relevant examples include Bcr-Abl (CML), amplified HER2/neu (breast cancer), overexpressed or mutated EGF receptors (lung cancer), and mutated BRAF (melanoma). Panel B. Genes are said to have a synthetic lethal relationship when mutation of either gene alone is tolerated by the cell, but mutation of both genes leads to lethality. Thus, in the example, mutant gene a and gene b have a synthetic lethal relationship, implying that the loss of one gene makes the cell dependent on the function of the other gene. In cancer cells, loss of function of a tumor-suppressor gene (wild-type designated gene A; mutant designated gene a) may render the cancer cells dependent on an alternative pathway of which gene B is a component. As shown in the figure, if an inhibitor of gene B can be identified, this can cause death of the cancer cell, without harming normal cells (which maintain wild-type function for gene A). High-throughput screens can now be performed using isogenic cell line pairs in which one cell line has a defined defect in a tumor-suppressor pathway. Compounds can be identified that selectively kill the mutant cell line; targets of these compounds have a synthetic lethal relationship to the tumor-suppressor pathway, and are potentially important targets for future therapeutics. Note that this approach allows discovery of drugs that indirectly target deleted tumor-suppressor genes and hence greatly expands the list of physiologically relevant cancer targets. Source: Chapter 84. Cancer Cell Biology and Angiogenesis, Harrison's Principles of Internal Medicine, 18e Citation: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. Harrison's Principles of Internal Medicine, 18e; 2012 Available at: http://accesspharmacy.mhmedical.com/DownloadImage.aspx?image=/data/books/harr/harr_c084f003b.gif&sec=40733930&BookID=331&ChapterSecID=40726820&imagename= Accessed: November 01, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved