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Originally published as JCO Early Release 10.1200/JCO.2005.09.961 on November 15 2004 © 2005 American Society of Clinical Oncology.
Targeted Therapy With Imatinib: Hits and Misses?Fox Chase Cancer Center, Philadelphia, PA Targeted therapeutics are highly specific inhibitors of particular molecules and are, therefore, not broadly effective in diverse malignancies. Extensive preclinical and clinical studies provide both clear examples of their efficacy and resounding examples of their shortcomings. Targeted therapies will require that we use them in a markedly different fashion than we use conventional drugs and will be successful only when they are used against biologically relevant targets in specific disease contexts. Imatinib mesylate (imatinib) is a success of targeted therapy. It is active against a number of related tyrosine kinases, namely ABL, BCR-ABL, KIT, PFGFR, and TEL. Imatinib has significant clinical efficacy in chronic myelogenous leukemia (CML)1 and gastrointestinal stromal tumors (GISTs).2 The reason that CML and GIST are effectively treated with imatinib is that they each contain a genetic change involving the targeted kinases that is integral to the biology of the malignancy. CML contains a translocation between the breakpoint cluster region and the ABL gene that leads to a constitutively active kinase. GISTs commonly express mutated KIT that is constitutively activated; some contain a wild-type KIT and/or a mutated platelet-derived growth factor receptor alpha (PDGFRA). The activity of these kinases provides the malignant cells with growth and survival signals. However, it is this activity that is so very effectively turned off by imatinib. The significant responses in patients with CML and GIST earned the agent rapid approval by the United States Food and Drug Administration, as well as significant notoriety in both the medical and lay press. Many have sought to use the drug in hopes of having similar dramatic responses in other cancers. Sihto et al3 report in this issue of the Journal of Clinical Oncology an analysis of a large collection of solid tumors for the presence of the imatinib targets KIT and PDGFR. Prior reports have examined the expression of KIT in specific tumor types, but this is the first study that cataloged these receptors in a large spectrum of solid tumors. Sihto et al used immunohistochemistry to detect KIT; at the present time, there are no antibodies useful for identifying PDGFR by this technique. Only three tumor types screened demonstrated multiple specimens with KIT immunostaining: GIST, small-cell lung cancer, and testicular teratocarcinoma. One to two cases of glioblastoma, medulloblastoma, breast cancer, non–small-cell lung cancer, and Merkel cell carcinoma also had KIT. Importantly, Sihto et al3 also analyzed the KIT and PDGFRA genes. Efficacy of imatinib varies with the site of KIT and PDGFRA mutation.4-8 In vitro data demonstrate that imatinib can inhibit the phosphorylation of wild-type receptors activated by ligand and that of mutated receptors in the absence of ligand. However, imatinib is less effective at inhibiting the phosphorylation of receptors with mutations in the enzymatic site (exon 17 mutations).7 GISTs, in which 95% of tumors express KIT, are not equally responsive to imatinib.8,9 Response and survival with metastatic GIST is best in patients whose tumors contain exon 11 mutations, compared with wild-type or other mutation sites. Sihto et al found that no tumor types had mutations in the KIT or PDGFRA, other than GISTs. Those tumors with KIT immunostaining, but without mutations, were found to have a high frequency of KIT gene amplification or multiple copies of chromosome 4, where the genes for KIT and PDGFR are located. The authors appropriately conclude that imatinib should not be used for treatment of most malignancies outside of the clinical trial setting. The strong correlation of clinical response with particular mutation sites is a consequence of how imatinib interacts with KIT.10 Mol et al recently published the molecular structures of KIT alone and KIT interacting with imatinib. Normally, KIT exists as an inactive membrane-bound receptor in which the juxtamembrane domain of the molecule inserts into the kinase domain, blocking its activity. In becoming activated, KIT is bound by its ligand, steel factor, dimerizes, and phosphorylates its own tyrosine residues. Mutated KIT receptors exist in the activated form in the absence of ligand; many mutations alter the structure of the juxtamembrane domain such that it no longer inhibits the kinase domain. Tumors with KIT-bearing mutations in the juxtamembrane domain, particularly exon 11 mutations, are effectively inhibited by imatinib, whereas wild-type KIT or mutants in other regions are not. Exon 17 mutations lead to activation of the molecule that is independent of the dimerization domain and therefore are not affected by imatinib therapy. When imatinib binds the wild-type receptor, it actually disrupts the receptor's natural auto-inhibition, which may explain why imatinib is less effective in tumors with wild-type receptors. This suggests that imatinib is not the best drug for tumors with wild-type KIT. New KIT inhibitors with binding properties that differ from imatinib might be more effective against wild-type and other forms of KIT. There are varied and specific requirements for targeted therapies to be effective. Hormone therapies in breast cancer are useful when at least 10% of tumor cells express the estrogen and progesterone receptors. Overexpression of Her-2/neu protein is used as an indicator of potential benefit of trastuzumab in breast cancer, but tumors with Her-2/neu gene amplification are most likely to respond. And, as was recently demonstrated, response to gefitinib in non–small-cell lung cancer requires not only the presence of the epidermal growth factor receptor (EGFR) but particular mutations in the EGFR gene.11,12 Furthermore, different classes of EGFR inhibitors result in dramatically different responses in colorectal cancer.13 Thus to best use targeted therapies, we need to know where their targets are expressed and to understand their particular requirements for effectiveness. Sihto et al3 have added to our understanding of the relevance of KIT and PDGFR in solid tumors, showing there is little role for imatinib in these tumor types, as there is no evidence for activating mutations in KIT and PDGFR except in GIST. Their survey of solid tumors found KIT is not usually present; when KIT was present by immunohistochemistry, there were no cases with activating mutations except in GIST. The two PDGFR mutations identified were also in GIST. Small-cell lung cancers were one tumor type with expression of KIT. Although there are preclinical data to support the use of imatinib for the therapy of small-cell lung cancer, there are few cases with KIT mutations,14,15 and the one clinical trial reported in abstract form demonstrated no responses, although the study was limited by a small number of patients with tumors expressing KIT.16 Further study will determine whether the other mechanisms delineated by the authors that may result in KIT and PDGFR activation can be therapeutically inhibited. Tumor cells are not the only cells that express imatinib targets. PDGFRs have been shown to be important in peritumoral vasculature.17,18 Preclinical studies have illustrated that treatment with antiangiogenic combinations can cause regressions of advanced tumors and decrease metastases.19,20 CML patients treated with imatinib have had normalization of microvessels and reticulin in their bone marrows.21 PDGFR beta signaling in peritumoral vasculature also leads to an increase in interstitial pressure. Preclinical data demonstrate that imatinib is able to decrease interstitial pressure and can lead to greater drug uptake in tumors.22,23 Chemotherapy combined with imatinib in murine models has revealed higher response rates and fewer metastases compared with either agent.20,24 Clinical trials are now testing the combination of imatinib with chemotherapeutic agents or antibodies. Targeted therapies require that we identify the appropriate patient to be treated and that we clearly understand the impact of affecting targets, not only on cancer cells but also in the surrounding stroma. The question remains: will we continue to prescribe therapy in a generalized fashion, or will customized regimens for each patient be required? We need to better understand who will benefit and who will not. If a therapy is relatively nontoxic, a 10% response rate in a nonselected patient population may not be unacceptable; however, if the likelihood of severe toxicities is equivalent to its likelihood of benefit, we may be harming more patients than we help if we do not select the patients likely to benefit. For some drugs, determining who will benefit is straightforward, such as hormone receptor status. For others, it is becoming more complicated. Although detecting EGFR is standard, it requires more to determine whether the crucial somatic mutation is present in non–small-cell lung cancer. We need to determine the cost-benefit ratio of doing the additional testing to select patients for targeted therapeutics and determine how we are going to test tissues from the majority of patients who are treated in community settings and not at academic research institutions. We are in an age of renewed hope about cancer therapy with many novel targeted agents available. To realize these hopes, it is our challenge to thoughtfully match targeted agents with the biology of malignant tumors and their hosts. Author's Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a finanical interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Margaret von Mehren, Novartis. Honoraria: Margaret von Mehren, Novartis. Research Funding: Margaret von Mehren, Novartis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue. REFERENCES
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2. Demetri G, vonMehren M, Blanke C, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002
3. Sihto H, Sarlomo-Rikala M, Tynninen O, et al: KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplification in human solid tumors. J Clin Oncol 23:49-57, 2005 4. Zermati Y, De Sepulveda P, Feger F, et al: Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene 22:660-664, 2003[CrossRef][Medline] 5. Ueda S, Ikeda H, Mizuki M, et al: Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296. Int J Hematol 76:427-435, 2002[Medline]
6. Frost M, Ferrao P, Hughes T, et al: Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-Kit where as the kinase domain mutant D816VKit is resistant. Mol Cancer Ther 1:1115-1124, 2002
7. Ma Y, Zeng S, Metcalfe DD, et al: The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99:1741-1744, 2002
8. Heinrich M, Corless C, Demetri G, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 9. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40:689-695, 2004
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12. Paez J, Janne P, Lee J, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 13. Cohen R: Epidermal growth factor receptor as a therapeutic target in colorectal cancer. Clin Colorectal Cancer 2:246-251, 2003[Medline] 14. Boldrini L, Ursino S, Gisfredi S, et al: Expression and mutational status of c-kit in small-cell lung cancer: Prognostic relevance. Clin Cancer Res 10:4101-4108, 2004[CrossRef][Medline]
15. Abrams TJ, Lee LB, Murray LJ, et al: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471-478, 2003 16. Johnson B, Fisher B, Fisher T, et al: Phase II study of STI571 (Gleevec) for patients with small cell lung cancer. Proc Am Soc Clin Oncol 21:A1171, 2002 (abstr 1171) 17. Dudley A, Gilbert R, Thomas D, et al: STI-571 inhibits in vitro angiogenesis. Biochem Biophys Res Commun 310:135-142, 2003[CrossRef][Medline]
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19. Uehara H, Kim S, Karashima T, et al: Effects of blocking platelet-derived growth factor receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95:458-470, 2003 20. Bergers G, Song S, Meyer-Morse N, et al: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-1295, 2003[CrossRef][Medline]
21. Kvasnicka H, Thiele J, Staib P, et al: Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. Blood 103:3549-3551, 2004
22. Pietras K, Ostman A, Sjoquist M, et al: Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929-2933, 2001
23. Pietras K, Stumm M, Hubert M, et al: STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res 9:3779-3787, 2003
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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