KRAS Oncogene Cancers Vulnerable to Attack on Genetic Partners
The TBK1 gene, identified as being essential for the survival of KRAS oncogene cancers, joins the list of targets for future therapies.
Cancer-causing mutations in the KRAS gene typically predict a poor response to most modern cancer therapies, but a study incorporating a large-scale RNA-interference (RNAi) assay has identified that expression of the TBK1 gene is essential for the survival of KRAS oncogene-based cancers. This gene is likely to be an easier therapeutic target than the notoriously resistant KRAS, opening up new avenues of attack on such cancers.
The TBK1 gene is the second potential avenue of attack on the KRAS oncogene that Prof William Hahn (Dana-Farber Cancer Institute, Harvard University, MA, USA), senior author of the study, has been involved in uncovering. Previously part of a research team headed by Prof D Gary Gilliland (Brigham and Women‘s Hospital, Harvard University, MA, USA) who unveiled their research into the role of the similar STK33 gene earlier this year, he has since pursued this area further with his own group.
Like all cells, cancer cells depend upon the normal functioning of a great many genes in order to survive. One option for developing effective cancer therapy, then, would be to identify the ways in which the requirements of these cancerous cells differ from those of normal ones.
While the central mutation(s) that allow common types of cancer to escape apoptosis and continue dividing are generally well-known, this information is not always helpful in developing therapy. Although some such mutated genes are easily deactivated, others (such as KRAS) are extremely resistant to these measures. This does not mean that the problem is intractable, however, as it is quite possible for the mutation which allows survival as a cancer to create new (or, at least, more serious) dependencies on the functioning of other genes that healthy cells do not possess.
The purpose of Hahn‘s study was to identify any genes that supported such dependencies from the KRAS oncogene, a search that involved the RNAi silencing-based analysis of an array of thousands of different genes across 20 cancerous and normal cell lines. The initial analysis identified 45 candidate genes, from which a second round of testing identified the TBK1 gene as being essential to the viability of KRAS cancers. On the subject of the size of the assay, Hahn commented: “Until 4 or 5 years ago, you couldn‘t have contemplated doing an experiment like this on so large a scale”.
Given this repeated success at tracking down genes essential for cancer viability, it is no surprise that Hahn has plans to carry out larger-scale assays of a wider range of cell lines in an effort to identify still more therapeutic targets in this promising area.
Since both cancer co-dependence genes identified thus far have been for kinases, an assay for the effectiveness of extant kinase inhibitors in anticancer activity is also planned. Should further theoretical progress be made on cancer co-dependence genes, the intention is to have a practical tool-kit ready for use.
Source: Barbie DA, Tamayo P, Boehm JS et al.: Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269), 108–112 (2009).
Potential Drug Target Found to Treat Impaired Nerve Cells
A team of scientists from Johns Hopkins University School of Medicine (MD, USA) have recently reported to have discovered a potential new drug target for the treatment of mental illnesses. In their study, they used a commercially available drug (rapamycin; known to act on mTOR) to successfully treat mammalian brain cells that were intentionally damaged by manipulating a newly discovered gene (KIAA1212) that is thought to have a link with the susceptibility genes (DISC1 and AKT) for schizophrenia and autism.
The discovery of this new gene, KIAA1212, led the scientists to test the effectiveness of the drug in saving impaired nerve cells, since it appeared that KIAA1212 acted in concert with DISC1 and AKT. Since mTOR is a well-known downstream effector of AKT, the scientists treated adult mice with abnormal neurons with rapamycin, a drug known to alleviate the effects of a dysfunctional AKT pathway. They were surprised to see that it effectively rescued the impaired neurons from their defective functions. “What was amazing to us is how potent the drug is, at least on the cellular level”, exclaimed Dr Hongjun Song, an associate professor of Neurology in the Institute for Cell Engineering at the Johns Hopkins, who collaborated in the research.
Their study identified the AKT–mTOR signaling pathway as a critical DISC1 target in regulating neuronal development. They also speculate that their research provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
“Our discoveries give us more of the information we need to understand the function of genes associated with psychological diseases”, explained Dr Guo-li Ming, co-investigator and an associate professor of neurology and neuroscience in the Institute for Cell Engineering at Johns Hopkins. “The next step is to create a good animal model that would allow us to test whether candidate drugs will reverse not only the irregularities of brain cells with deficiency of these genes, but also behaviors”, Ming concluded.
Source: Kim JY, Duan X, Liu CY et al.: DISC1 regulates new neuron development in the adult brain via modulation of AKT–mTOR signaling through KIAA1212. Neuron 63(6), 761–773 (2009).
Influence of Genetics on Plavix®/Effient® Treatment to be Examined by Medco Comparative Effectiveness Study
The Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes (GeCCO) study, undertaken by Medco Health Solutions, Inc. (NJ, USA), plans to enroll more than 14,000 acute coronary syndrome patients who have been newly prescribed either Plavix® (clopidogrel, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, NY, USA) and Effient® (prasugrel, Eli Lilly and Company, IN, USA). “These drugs are an important part of therapy for people with recent coronary events to prevent further cardiovascular problems”, explained Dr Robert Epstein, Medco‘s chief medical officer.
The aim of the study is to compare the effectiveness of the two drugs by measuring the rate of cardiovascular deaths, nonfatal heart attacks and nonfatal strokes over a 6-month period. Patient enrollment is planned to start late 2009 and is scheduled to end in mid 2011 with the results hoped to be presented by early 2012. Patients enrolled in the study using clopidogrel will be required to provide a saliva sample to determine if their genetics causes them to metabolize the drug effectively. Patients using prasugrel will not need to use a gene test since the drug is metabolized by a different pathway that is not affected by genetic variations.
“This study could have a huge bearing on patient safety and the costs to treat this condition. Plavix is going generic in 2011, and if found to be equally effective as Effient for patients who have a normally functioning version of the CYP2C19 gene, the study provides the evidence that would allow these patients to opt for a lower cost treatment. This study is a great example of Medco‘s new Genetics for Generics strategy, optimizing clinical outcomes of generic drugs while lowering overall healthcare costs”, commented Dr Epstein.
Plavix‘s labeling was revised in May 2009 to provide information to prescribers regarding how variations of the CYP2C19 gene can affect the action of the drug. The GeCCO study aims to also collect new information on the type of physician action taken and clinical outcomes in the 25–30% of patients who do not extensively metabolize clopidogrel because of their CYP2C19 genotype.
Source: Medco Press Release: http://medco.mediaroom.com/index.php?s=43&item=403
ATR DNA Repair Protein: Possible New Target for Cancer Therapy?
While the loss of either the p53 tumor suppressor or ATR DNA repair protein is a serious event, the loss of both causes fatal tissue deterioration in mice, a recent study carried out by Prof Eric Brown‘s group (University of Pennsylvania, PA, USA) suggests.
The loss of two proteins with such closely-related functions – the repair of DNA damage by ATR, and the detection and removal of cells with irreparable damage by p53 – would always be a serious problem for any organism that relies on them, but Brown‘s recent study into rapidly-growing tissues such as hair follicles, intestinal walls and skin indicates that the losses have a synergistic negative effect.
Naturally, the loss of an essential DNA repair protein like ATR will cause many problems for the affected cells, with a much greater incidence of irreparable DNA damage and subsequent apoptosis. One might suspect that the removal of the mechanism responsible for this apoptosis would then rescue this situation to some extent – a great many mutations and nonviable cells would produce a ‘messy‘ result, but overall the reduction of apoptosis would increase survival by allowing cells with minor DNA damage to continue to contribute to the functioning of the tissue. Indeed, this has been found to be the case for other DNA repair proteins – tissue function when such a protein has been lost is superior when p53 function is also lost.
In the case of ATR, however, the reverse is true. This suggests that, when the unrepaired DNA damage is serious enough, maintaining the function of cells with minor damage becomes secondary in importance to the removal of those rendered nonfunctional, as an essential precursor to effective regeneration. Under such circumstances, a breakdown in this ‘housekeeping‘ could lead to a disastrous breakdown in regeneration as well, with the cells rendered useless by ineffective repair persisting in the tissue and acting either as a physical barrier – taking up space needed for the growth of new cells – or a chemical one, releasing signals that prevent new cells from growing near them.
A potential practical application for this research may come in the form of using ATR modulation to combat cancer. A sizeable percentage of cancers possess p53 mutations resulting in loss of function for that gene. While this is often the factor that permits them to continue to survive, it could be that, as Brown speculates, “p53-deficient tumors might be especially susceptible to ATR inhibition”. Obviously, such therapy would not be without its risks – even temporarily disabling major DNA repair enzymes could cause serious problems in itself – but should the degree of increased vulnerability of certain cancers to this treatment prove to be large enough, there may well be situations in which it is a viable option.
A likely means by which this result may be achieved is the inhibition of chk1, a partner protein of ATR and the target of a clinical trial that is already underway.
Source: Ruzankina Y, Schoppy DW, Asare A, Clark CE, Vonderheide RH, Brown EJ: Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53. Nat. Genet. 41(10), 1144–1149 (2009).