|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.18.6585 on October 27 2008 © 2008 American Society of Clinical Oncology.
Targeting Polo-Like Kinase: Learning Too Little Too Late?
The Drug Development Unit, Royal Marsden National Health Services Foundation Trust and The Institute of Cancer Research, Surrey, United Kingdom
Cancer Research UK Translational Cancer Therapeutics Laboratory, London Research Institute, London, United Kingdom
The Drug Development Unit, Royal Marsden National Health Services Foundation Trust and The Institute of Cancer Research, Surrey, United Kingdom This issue of Journal of Clinical Oncology reports on the results of two phase I clinical trials (first in man and first in class) of different polo-like kinase (PLK) small-molecule inhibitors.1,2 PLK1 to PLK4 are serine/threonine kinases with wide-ranging activities during mitosis, regulating entry into mitosis, centrosome duplication required for bipolar mitotic spindle formation, transition from metaphase to anaphase, cytokinesis, and maintenance of genomic stability.1 Consistent with this role, peak expression of PLK1 mRNA and protein occurs in mitosis.2 Antimitotic drugs remain arguably one of the most successful classes of anticancer drugs. The identification of multiple novel kinases critical to mitosis, including the PLK family and the Aurora kinases, and motor proteins such as the kinesins including KSP and CENP-E, has led to the recent clinical evaluation of multiple small-molecule inhibitors of these targets. To date, these novel antimitotics have primarily had neutropenia reported as their primary toxicity with modest antitumor activity. PLK1 is the best studied among the four PLK family members, and although it is not clear whether it is important or indeed beneficial to inhibit all of the other PLKs,2-4 there is substantial preclinical evidence to support PLK as a validated target for anticancer drug development. PLK1 is overexpressed in tumors of diverse origin, is absent in adjacent normal tissue,3 and correlates with poor outcome.4-7 Forced overexpression of PLK1 in NIH3T3 cells promotes transformation, soft agar growth, and tumor formation in nude mice.8 Moreover, silencing of PLK1 expression by RNA interference inhibits tumor cell proliferation and induces a G2/M arrest.9-11 Functional genomic RNA interference kinome and whole genome screens have reported that the silencing of PLK1 inhibits cancer cell viability in breast (CAL51 and MDA-MB-231), colorectal (HCT-116), and non–small-cell lung cancer (NCI-H1155) cell lines, ranking in the top 5% to 10% of genes tested.12-14 Only two of these cell lines (MDA-MB-231 and NCI-H1155) have mutant p53, indicating that p53 status may not be a determinant of sensitivity to PLK silencing. Nonetheless, several groups have provided evidence for tumor cell dependency and selective cytotoxicity. PLK silencing in nontransformed breast epithelial cell lines had less effect on cell proliferation than in breast cancer cell lines.10 Nontransformed immortalized epithelial cell lines have also been reported to fail to arrest in mitosis after PLK1 depletion, in contrast to the HeLa cancer cell line, which arrested in mitosis and engaged in mitotic catastrophe.11 Depletion of PLK1 in normal human cells did not result in detectable cell cycle defects,15 but depletion of PLK1 did result in antitumor activity in multiple xenograft models.15,16 Jimeno et al17 describe a phase I study with an accelerated titration dose-escalation design of ON 01910.Na, a small-molecule PLK1 inhibitor that is not an adenosine triphosphate–mimetic inhibitor but is believed to compete for the substrate-binding site of PLK1.18 The second phase I study by Mross et al19 explores BI 2536, a highly potent (low nanomolar inhibitory concentration by 50%) adenosine triphosphate kinase inhibitor of PLK1, PLK2, and PLK320 in a traditional 3 + 3 escalation scheme. Traditional phase I trial designs were pursued in both trials with pharmacokinetic evaluation; pharmacodynamic studies were not pursued in either trial. Despite this, in the trial of BI 2536, the typical toxicity of mitotic inhibitors, neutropenia, was reported as the dose-limiting toxicity; this supports target blockade in surrogate tissue with BI 2536 and further evaluation in phase II trials. However, myelosuppression was not observed in the ON 01910.Na phase I trial, raising concern that this drug is not impacting mitosis in proliferating bone marrow. Moreover, the lack of a pharmacodynamic audit trial from tumor tissue in both studies means that these studies have not concluded that the recommended dose levels result in tumor cell PLK1 inhibition.21 Confirmation of PLK1 inhibition in tumor cells at the recommended phase II dose levels must remain a priority for the future development of these agents; this could be pursued by evaluating phospho-histone H3 and Ki67 expression in tumor biopsies or circulating tumor cells or fluorothymidine positron emission tomography (FLT-PET). An evaluation of the impact of PLK1 blockade on mitotic arrest, ploidy, mitotic catastrophe, and apoptosis using biomarkers such as the caspase cleaved cytokeratin M30 in tumor cells could also be extremely valuable to determine whether treatment is inducing mitotic arrest, apoptosis, or no target blockade. Critically, however, these biomarkers need to be analytically validated before they can be useful. Overall, therefore, it seems that, in at least one of these phase I studies, the data have not rejected the no go decision, supporting progression to phase II evaluation. Nevertheless, the described preliminary evidence of antitumor activity does traditionally support the further evaluation of these agents, although this may not necessarily be related to PLK1 blockade. Biomarker studies could also support optimization of PLK1 inhibitor administration schedules. Trials of antimitotics have adopted different administration schedules, suggesting that the optimal schedule for these agents remains undefined. Because prolonged PLK silencing and mitotic arrest has been shown to result in DNA damage,22 longer duration of target blockade may be necessary to maximize antitumor activity. Therefore, demonstration of PLK1 inhibition alone in these biomarker studies may not be sufficient to predict patient benefit. Many major questions remain. Do tumor cells exposed to these agents at the administered doses and schedules result in PLK1 blockade, mitotic arrest, mitotic catastrophe, or apoptosis? The exact mechanisms of cancer cell death and mitotic catastrophe after mitotic arrest induced by these agents remain unclear. Both PLK inhibitors and microtubule-stabilizing agents induce mitotic arrest followed by cell death,13,20 promoting p53 stabilization, BAX expression, and pro-caspase 8 cleavage, which is indicative of activation of the mitochondrial and death receptor apoptotic pathways.9,23,24 Wild-type p53 function does not seem to be required for cell death mediated by either taxanes or after PLK1 inhibition.11,15 Given the similarities between the known cell death pathways induced by antimitotics, it will be important to define biomarkers predictive of response and to identify whether these new agents demonstrate efficacy in disease resistant to traditional antitubulin cytotoxics.25 Studies also indicate that cell death after PLK knockdown can be enhanced by inhibiting the DNA damage response kinase ATM, suggesting that cells with defective DNA damage response signaling may be more sensitive to PLK inhibitors.9 Furthermore, because PLK inhibition results in a metaphase mitotic arrest, the combination of PLK inhibition with taxanes or trastuzumab in HER2-expressing cell lines may be a viable synergistic strategy that seems not to promote significant additional cytotoxicity in immortalized nontransformed breast epithelial cell lines.10 However, cytotoxic combinatorial strategies may be limited by myelosuppression.26 Overall, it seems that we are still learning too little too late in the drug development process. Improved understanding of how disruption of cancer cell mitosis leads to cell death in sensitive tumors and how these pathways are subverted in resistant disease is critical to the future success of drugs targeting mitotic transition. Moreover, implementation of pharmacodynamic end points into clinical trials of antimitotic therapies is needed to answer key biologic issues and to define doses and schedules. Identification of biomarkers to predict therapeutic response from both traditional and new antimitotic therapies is also required to define sensitive patient cohorts. Finally, the similarities between cell death pathways associated with antimitotic agents in routine clinical use and those in development and the likelihood of shared resistance mechanisms should raise concern and should be further evaluated when designing future clinical trials examining the efficacy of agents targeting the mitotic apparatus. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Johann de Bono, Boehringer Ingleheim (C) Stock Ownership: None Honoraria: Johann de Bono, Boehringer Ingleheim Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: David Olmos, Charles Swanton, Johann de Bono Final approval of manuscript: David Olmos, Charles Swanton, Johann de Bono ACKNOWLEDGMENTS Both D.O. and C.S contributed equally to this Editorial. NOTES published online ahead of print at www.jco.org on October 27, 2008 REFERENCES 1. Barr FA, Sillje HH, Nigg EA: Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5:429-440, 2004[CrossRef][Medline] 2. Lake RJ, Jelinek WR: Cell cycle- and terminal differentiation-associated regulation of the mouse mRNA encoding a conserved mitotic protein kinase. Mol Cell Biol 13:7793-7801, 1993 3. Holtrich U, Wolf G, Brauninger A, et al: Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci U S A 91:1736-1740, 1994 4. Kanaji S, Saito H, Tsujitani S, et al: Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma. Oncology 70:126-133, 2006[CrossRef][Medline] 5. Weichert W, Kristiansen G, Schmidt M, et al: Polo-like kinase 1 expression is a prognostic factor in human colon cancer. World J Gastroenterol 11:5644-5650, 2005[Medline] 6. Yamada S, Ohira M, Horie H, et al: Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: Identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene 23:5901-5911, 2004[CrossRef][Medline] 7. Liu L, Zhang M, Zou P: Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk Lymphoma 48:2179-2183, 2007[CrossRef][Medline] 8. Smith MR, Wilson ML, Hamanaka R, et al: Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase. Biochem Biophys Res Commun 234:397-405, 1997[CrossRef][Medline] 9. Liu X, Erikson RL: Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 100:5789-5794, 2003 10. Spänkuch B, Kurunci-Csacsko E, Kaufmann M, et al: Rational combinations of siRNAs targeting Plk1 with breast cancer drugs. Oncogene 26:5793-5807, 2007[CrossRef][Medline] 11. Liu X, Lei M, Erikson RL: Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol 26:2093-2108, 2006 12. Turner NC, Lord CJ, Iorns E, et al: A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Embo J 27:1368-1377, 2008[CrossRef][Medline] 13. Swanton C, Marani M, Pardo O, et al: Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 11:498-512, 2007[CrossRef][Medline] 14. Whitehurst A, Bodemann B, Cardenas J, et al: Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446:815-819, 2007 15. Guan R, Tapang P, Leverson JD, et al: Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res 65:2698-2704, 2005 16. Spänkuch B, Matthess Y, Knecht R, et al: Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1. J Natl Cancer Inst 96:862-872, 2004 17. Jimeno A, Li J, Messersmith WA, et al: Phase I study of ON 01910.Na, a novel modulator of the polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol doi:10.1200/JCO.2008.17.9788 [epub ahead of print on October 27, 2008] 18. Gumireddy K, Reddy MV, Cosenza SC, et al: ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 7:275-286, 2005[CrossRef][Medline] 19. Mross K, Frost A, Steinbild S, et al: Phase I dose escalation and pharmacokinetic study of BI 2536, a novel polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol doi:10.1200/JCO.2008.16.1547 [epub ahead of print on October 27, 2008] 20. Steegmaier M, Hoffmann M, Baum A, et al: BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 17:316-322, 2007[CrossRef][Medline] 21. Sarker D, Workman P: Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res 96:213-268, 2007[CrossRef][Medline] 22. Dalton WB, Nandan MO, Moore RT, et al: Human cancer cells commonly acquire DNA damage during mitotic arrest. Cancer Res 67:11487-11492, 2007 23. Chen JG, Yang CP, Cammer M, et al: Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res 63:7891-7899, 2003 24. Blagosklonny MV: Prolonged mitosis versus tetraploid checkpoint: How p53 measures the duration of mitosis. Cell Cycle 5:971-975, 2006[Medline] 25. Harrison M, Swanton C: Epothilones and new analogues of the microtubule modulators in taxane-resistant disease. Expert Opin Investig Drugs 17:523-546, 2008[CrossRef][Medline] 26. Blagden SP, Molife LR, Seebaran A, et al: A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 98:894-899, 2008[CrossRef][Medline]
Related Articles
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
