Abstract
Over the past two decades, progresses in colorectal cancer treatment have significantly improved patient survival and quality of life. However, unresectable metastatic colorectal cancer remains virtually incurable, making the search for new effective therapeutics mandatory. An important limitation to the development of new agents has been the difficulty to exploit mutated tumor suppressors or “undruggable” oncogenes as a target. Recently, evidence that mutations in tumor suppressors, such as BRCA1/2, make cancer cells highly susceptible to inhibitors of a compensatory DNA repair pathway [poly-(ADP-ribose) polymerase 1 (PARP1)] has broadened the range of possible therapeutic targets by extending it to gene products that are in a “synthetic lethal” relationship with oncogenes and tumor suppressors. Inhibition of such targets blocks specific buffer-mechanisms that are required for survival in the presence of defined oncogenic mutations, but not in their absence. As a consequence, selective elimination of mutation-bearing cells results. This approach has led to identify compounds that are highly active in the presence of different types of mutated tumor suppressors and oncogenes, including DNA repair genes, RAS, and Myc. In addition, ongoing studies promise to identify new mechanisms which, when pharmacologically interfered with, will selectively eradicate mutated cancer cells. Here, we revise and discuss these new aspects of cancer biology and highlight their potential applications in colorectal cancer treatment.
Keywords: Colorectal cancer, drug screenings, molecularly targeted agents, MYC, RAS, synthetic lethality
Current Cancer Drug Targets
Title:Synthetic Lethality-Based Therapeutics: Perspectives for Applications in Colorectal Cancer
Volume: 12 Issue: 4
Author(s): D. Soncini, I. Caffa, F. Patrone, A. Ballestrero and A. Nencioni
Affiliation:
Keywords: Colorectal cancer, drug screenings, molecularly targeted agents, MYC, RAS, synthetic lethality
Abstract: Over the past two decades, progresses in colorectal cancer treatment have significantly improved patient survival and quality of life. However, unresectable metastatic colorectal cancer remains virtually incurable, making the search for new effective therapeutics mandatory. An important limitation to the development of new agents has been the difficulty to exploit mutated tumor suppressors or “undruggable” oncogenes as a target. Recently, evidence that mutations in tumor suppressors, such as BRCA1/2, make cancer cells highly susceptible to inhibitors of a compensatory DNA repair pathway [poly-(ADP-ribose) polymerase 1 (PARP1)] has broadened the range of possible therapeutic targets by extending it to gene products that are in a “synthetic lethal” relationship with oncogenes and tumor suppressors. Inhibition of such targets blocks specific buffer-mechanisms that are required for survival in the presence of defined oncogenic mutations, but not in their absence. As a consequence, selective elimination of mutation-bearing cells results. This approach has led to identify compounds that are highly active in the presence of different types of mutated tumor suppressors and oncogenes, including DNA repair genes, RAS, and Myc. In addition, ongoing studies promise to identify new mechanisms which, when pharmacologically interfered with, will selectively eradicate mutated cancer cells. Here, we revise and discuss these new aspects of cancer biology and highlight their potential applications in colorectal cancer treatment.
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Soncini D., Caffa I., Patrone F., Ballestrero A. and Nencioni A., Synthetic Lethality-Based Therapeutics: Perspectives for Applications in Colorectal Cancer, Current Cancer Drug Targets 2012; 12 (4) . https://dx.doi.org/10.2174/156800912800190938
DOI https://dx.doi.org/10.2174/156800912800190938 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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