RobinP
07-26-2006, 11:23 AM
Will Kinase Inhibitors Have a Dark Side?
Charles L. Sawyers, M.D. [/url]A clear lesson that has emerged from growing experience with small-molecule kinase inhibitors is that a detailed knowledge of the drug target predicts clinical success in cancer treatment. Tumors with mutations that activate a kinase (or other proteins in the signaling pathway in which the kinase resides) are most likely to respond when they are treated with an appropriate inhibitor of that particular kinase.
Among the next wave of kinase inhibitors to be clinically tested are those designed to block Akt (also called protein kinase B), a molecule with all the hallmarks of a critical cancer target. The most compelling evidence comes from genomic studies of human tumor samples. In one third to one half of all cancers, such studies have revealed mutations in AKT or in the Akt regulatory proteins phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN) (Figure 1 (http://content.nejm.org/icons/home/spacer.gif)). A recent report by Yoeli-Lerner et al.,1 (http://content.nejm.org/cgi/content/full/355/3/313#R1) however, raises concern. Even though the inhibition of Akt should foil local tumor growth, it could promote invasion and metastasis in certain settings.
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Figure 1. The Akt Pathway. The Akt pathway is frequently activated in certain cancers through mutations in AKT or in the genes encoding other members of the pathway, such as proteins PI3K and PTEN. PI3K and AKT encode oncogenes (green), whereas PTEN is a tumor-suppressor gene (red). A recent study by Yoeli-Lerner et al.[url="http://content.nejm.org/cgi/content/full/355/3/313#R1"]1 (http://content.nejm.org/cgi/powerpoint/355/3/313/F1) showed that when Akt kinase is active, the NFAT transcription factor is targeted to the proteosome, where it is degraded. When Akt kinase is inactive (because of inhibition by a small-molecule drug, for example), NFAT moves to the nucleus, where it drives the expression of genes that promote invasion and metastasis.
The first evidence of a potential antimetastatic function of Akt was provided by a transgenic mouse model of breast cancer, as described by Hutchinson et al.2 (http://content.nejm.org/cgi/content/full/355/3/313#R2) As expected, in mice with tumors that overexpress the human epidermal growth factor receptor 2 (HER2/neu), larger primary tumors developed in the setting of ramped-up Akt activity, yet the mice had relatively fewer metastatic lesions. Yoeli-Lerner et al. confirmed the antimetastatic action of Akt in several breast-cancer cell lines and elucidated a potential mechanism involving the nuclear factor of activated T cells (NFAT). The model implicates NFAT as a master switch that controls the expression of a set of genes that promotes invasion (Figure 1 (http://content.nejm.org/cgi/content/full/355/3/313#F1)). Akt normally holds NFAT in check by promoting its destruction in the proteosome, thereby suppressing invasion and metastasis. Akt inhibition allows NFAT to escape destruction, translocate to the nucleus, and activate a gene-expression program that leads to metastasis.
Although the studies by Yoeli-Lerner et al. and Hutchinson et al. are provocative, should they have an effect on the clinical evaluation of Akt inhibitors? It could be argued that they should not, on the basis of the dismal track record of preclinical models in the prediction of clinical outcomes associated with particular cancer drugs. However, there is growing optimism that genetically defined models, such as those described in the previously cited studies, may be more predictive than were earlier approaches. Assuming that the antimetastatic action of Akt observed in these breast-cancer models is relevant to human cancer, how might clinical trials be designed to detect such a signal?
Initial efficacy trials of Akt inhibitors will probably be conducted in patients with cancer who have not had a response to conventional therapy. Clinical activity will be scored by radiographic assessment of measurable disease and reported with the use of widely accepted criteria with regard to tumor shrinkage. To increase the probability of objective responses, much effort will focus on the enrichment of these trials with patients whose tumors are suspected to be Akt-dependent. This strategy is likely to require molecular assessment of tumor-biopsy specimens for abnormalities in AKT or genes encoding other members of the Akt pathway, since most tumor types have abnormalities in the Akt pathway only in a subgroup of cases. If initial clinical trials can identify patients with Akt-dependent cancers that shrink during several months of treatment with an Akt inhibitor, confirmatory phase 2 studies will be conducted and could lead the Food and Drug Administration to approve the drug for use in patients who have no other treatment options.
If Akt inhibition does enhance metastasis, this signal will be difficult to detect unless trials are specifically designed to assess this possibility. Frequent radiographic evaluation of patients who have a response to treatment will not be sufficient for follow-up, because the interpretation of newly incident lesions will be problematic. Without a randomized, untreated control group, it will be impossible to distinguish between the promotion of metastasis by Akt inhibition and normal disease progression. In addition, the activation of Akt pathways should be measured in new lesions to differentiate an effect of the drug from acquired drug resistance.
Although these concerns may raise fears of large, expensive, and potentially inconclusive clinical studies, it is worth considering the potential role of biomarkers to focus the analysis on subgroups that are at greatest risk. For example, patients with NFAT-negative tumors should be at reduced risk for the prometastatic consequences of Akt inhibition, since Akt would no longer exert direct control over the genes controlling invasion. Histologic analysis and genotyping of tumors could also play a role. On the basis of models used by Yoeli-Lerner et al. and Hutchinson et al., one could conclude that the antimetastatic actions of Akt may be relevant only in breast cancer or in tumors driven by HER2. Indeed, studies in other cell types suggest the opposite — that Akt inhibition could prevent metastasis in other types of tumors.
Although the yin–yang biology of Akt suggested by Yoeli-Lerner et al. is unexpected, it is not without precedent. The transforming growth factor http://content.nejm.org/math/beta.gif–receptor pathway restrains the development of tumors in normal epithelium, yet inhibitors of the pathway block tumor growth in models of late-stage cancer.3 (http://content.nejm.org/cgi/content/full/355/3/313#R3) In a similar way, an inhibitor of a kinase called the mammalian target of rapamycin (mTOR) blocks Akt-dependent tumor growth in mouse models but can stimulate Akt kinase activity.4 (http://content.nejm.org/cgi/content/full/355/3/313#R4),5 (http://content.nejm.org/cgi/content/full/355/3/313#R5) Inhibitors of both targets are being developed for clinical use. At first glance, the concerns raised by these preclinical observations are daunting. However, the issues can be explored in carefully designed clinical trials with the use of tools of modern genomics, provided that tissues are collected to allow for the appropriate measurements to be made.
Dr. Sawyers reports having received consulting fees from Exelixis. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medicine, Molecular Pharmacology, and Urology, University of California, Los Angeles, Los Angeles.
References
Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005;20:539-550. [CrossRef] (http://content.nejm.org/cgi/external_ref?access_num=10.1016/j.molcel.2005.10.033&link_type=DOI)[ISI] (http://content.nejm.org/cgi/external_ref?access_num=000233525400008&link_type=ISI)[Medline] (http://content.nejm.org/cgi/external_ref?access_num=16307918&link_type=MED)
Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 2004;64:3171-3178. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=canres&resid=64/9/3171)
Arteaga CL. Inhibition of TGFbeta signaling in cancer therapy. Curr Opin Genet Dev 2006;16:30-37. [CrossRef] (http://content.nejm.org/cgi/external_ref?access_num=10.1016/j.gde.2005.12.009&link_type=DOI)[ISI] (http://content.nejm.org/cgi/external_ref?access_num=000235435500006&link_type=ISI)[Medline] (http://content.nejm.org/cgi/external_ref?access_num=16377175&link_type=MED)
Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:10314-10319. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pnas&resid=98/18/10314)
O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-1508. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=canres&resid=66/3/1500)
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Charles L. Sawyers, M.D. [/url]A clear lesson that has emerged from growing experience with small-molecule kinase inhibitors is that a detailed knowledge of the drug target predicts clinical success in cancer treatment. Tumors with mutations that activate a kinase (or other proteins in the signaling pathway in which the kinase resides) are most likely to respond when they are treated with an appropriate inhibitor of that particular kinase.
Among the next wave of kinase inhibitors to be clinically tested are those designed to block Akt (also called protein kinase B), a molecule with all the hallmarks of a critical cancer target. The most compelling evidence comes from genomic studies of human tumor samples. In one third to one half of all cancers, such studies have revealed mutations in AKT or in the Akt regulatory proteins phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN) (Figure 1 (http://content.nejm.org/icons/home/spacer.gif)). A recent report by Yoeli-Lerner et al.,1 (http://content.nejm.org/cgi/content/full/355/3/313#R1) however, raises concern. Even though the inhibition of Akt should foil local tumor growth, it could promote invasion and metastasis in certain settings.
http://content.nejm.org/content/vol355/issue3/images/small/18f1.gif
View larger version (56K):
[in this window] (http://content.nejm.org/cgi/content/full/355/3/313/F1)
[in a new window] (http://content.nejm.org/cgi/content-nw/full/355/3/313/F1)
http://content.nejm.org/icons/powerpoint/get_pp_slide_center.gif
Figure 1. The Akt Pathway. The Akt pathway is frequently activated in certain cancers through mutations in AKT or in the genes encoding other members of the pathway, such as proteins PI3K and PTEN. PI3K and AKT encode oncogenes (green), whereas PTEN is a tumor-suppressor gene (red). A recent study by Yoeli-Lerner et al.[url="http://content.nejm.org/cgi/content/full/355/3/313#R1"]1 (http://content.nejm.org/cgi/powerpoint/355/3/313/F1) showed that when Akt kinase is active, the NFAT transcription factor is targeted to the proteosome, where it is degraded. When Akt kinase is inactive (because of inhibition by a small-molecule drug, for example), NFAT moves to the nucleus, where it drives the expression of genes that promote invasion and metastasis.
The first evidence of a potential antimetastatic function of Akt was provided by a transgenic mouse model of breast cancer, as described by Hutchinson et al.2 (http://content.nejm.org/cgi/content/full/355/3/313#R2) As expected, in mice with tumors that overexpress the human epidermal growth factor receptor 2 (HER2/neu), larger primary tumors developed in the setting of ramped-up Akt activity, yet the mice had relatively fewer metastatic lesions. Yoeli-Lerner et al. confirmed the antimetastatic action of Akt in several breast-cancer cell lines and elucidated a potential mechanism involving the nuclear factor of activated T cells (NFAT). The model implicates NFAT as a master switch that controls the expression of a set of genes that promotes invasion (Figure 1 (http://content.nejm.org/cgi/content/full/355/3/313#F1)). Akt normally holds NFAT in check by promoting its destruction in the proteosome, thereby suppressing invasion and metastasis. Akt inhibition allows NFAT to escape destruction, translocate to the nucleus, and activate a gene-expression program that leads to metastasis.
Although the studies by Yoeli-Lerner et al. and Hutchinson et al. are provocative, should they have an effect on the clinical evaluation of Akt inhibitors? It could be argued that they should not, on the basis of the dismal track record of preclinical models in the prediction of clinical outcomes associated with particular cancer drugs. However, there is growing optimism that genetically defined models, such as those described in the previously cited studies, may be more predictive than were earlier approaches. Assuming that the antimetastatic action of Akt observed in these breast-cancer models is relevant to human cancer, how might clinical trials be designed to detect such a signal?
Initial efficacy trials of Akt inhibitors will probably be conducted in patients with cancer who have not had a response to conventional therapy. Clinical activity will be scored by radiographic assessment of measurable disease and reported with the use of widely accepted criteria with regard to tumor shrinkage. To increase the probability of objective responses, much effort will focus on the enrichment of these trials with patients whose tumors are suspected to be Akt-dependent. This strategy is likely to require molecular assessment of tumor-biopsy specimens for abnormalities in AKT or genes encoding other members of the Akt pathway, since most tumor types have abnormalities in the Akt pathway only in a subgroup of cases. If initial clinical trials can identify patients with Akt-dependent cancers that shrink during several months of treatment with an Akt inhibitor, confirmatory phase 2 studies will be conducted and could lead the Food and Drug Administration to approve the drug for use in patients who have no other treatment options.
If Akt inhibition does enhance metastasis, this signal will be difficult to detect unless trials are specifically designed to assess this possibility. Frequent radiographic evaluation of patients who have a response to treatment will not be sufficient for follow-up, because the interpretation of newly incident lesions will be problematic. Without a randomized, untreated control group, it will be impossible to distinguish between the promotion of metastasis by Akt inhibition and normal disease progression. In addition, the activation of Akt pathways should be measured in new lesions to differentiate an effect of the drug from acquired drug resistance.
Although these concerns may raise fears of large, expensive, and potentially inconclusive clinical studies, it is worth considering the potential role of biomarkers to focus the analysis on subgroups that are at greatest risk. For example, patients with NFAT-negative tumors should be at reduced risk for the prometastatic consequences of Akt inhibition, since Akt would no longer exert direct control over the genes controlling invasion. Histologic analysis and genotyping of tumors could also play a role. On the basis of models used by Yoeli-Lerner et al. and Hutchinson et al., one could conclude that the antimetastatic actions of Akt may be relevant only in breast cancer or in tumors driven by HER2. Indeed, studies in other cell types suggest the opposite — that Akt inhibition could prevent metastasis in other types of tumors.
Although the yin–yang biology of Akt suggested by Yoeli-Lerner et al. is unexpected, it is not without precedent. The transforming growth factor http://content.nejm.org/math/beta.gif–receptor pathway restrains the development of tumors in normal epithelium, yet inhibitors of the pathway block tumor growth in models of late-stage cancer.3 (http://content.nejm.org/cgi/content/full/355/3/313#R3) In a similar way, an inhibitor of a kinase called the mammalian target of rapamycin (mTOR) blocks Akt-dependent tumor growth in mouse models but can stimulate Akt kinase activity.4 (http://content.nejm.org/cgi/content/full/355/3/313#R4),5 (http://content.nejm.org/cgi/content/full/355/3/313#R5) Inhibitors of both targets are being developed for clinical use. At first glance, the concerns raised by these preclinical observations are daunting. However, the issues can be explored in carefully designed clinical trials with the use of tools of modern genomics, provided that tissues are collected to allow for the appropriate measurements to be made.
Dr. Sawyers reports having received consulting fees from Exelixis. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medicine, Molecular Pharmacology, and Urology, University of California, Los Angeles, Los Angeles.
References
Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005;20:539-550. [CrossRef] (http://content.nejm.org/cgi/external_ref?access_num=10.1016/j.molcel.2005.10.033&link_type=DOI)[ISI] (http://content.nejm.org/cgi/external_ref?access_num=000233525400008&link_type=ISI)[Medline] (http://content.nejm.org/cgi/external_ref?access_num=16307918&link_type=MED)
Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 2004;64:3171-3178. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=canres&resid=64/9/3171)
Arteaga CL. Inhibition of TGFbeta signaling in cancer therapy. Curr Opin Genet Dev 2006;16:30-37. [CrossRef] (http://content.nejm.org/cgi/external_ref?access_num=10.1016/j.gde.2005.12.009&link_type=DOI)[ISI] (http://content.nejm.org/cgi/external_ref?access_num=000235435500006&link_type=ISI)[Medline] (http://content.nejm.org/cgi/external_ref?access_num=16377175&link_type=MED)
Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:10314-10319. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=pnas&resid=98/18/10314)
O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-1508. [Abstract/Full Text] (http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=canres&resid=66/3/1500)
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