- Email: [email protected]
Can the heat shock protein 90 inhibitor geldanamycin be designed to specifically inhibit HER-2 tyrosine kinase?
Geldanamycin and Her-2 inhibition
Can the heat shock protein 90 inhibitor geldanamycin be designed to specifically inhibit HER-2 tyrosine kinase? Leonard M. Neckers Department of cell and Cancer Biology, National Cancer Institute, Rockville, USA
G
eldanamycin (GA), a member of the benzoquinone ansamycin class of antibiotics, is known to bind to and specifically inhibit the molecular chaperone heat shock protein 90 (Hsp90).1 Hsp90 is a very abundant cellular constituent which, among other functions, serves to stabilize and support the activity of a number of tyrosine and serine/threonine kinases, including transmembrane receptors (e.g. HER-1, HER-2, insulin-like growth factor receptor, platelet-derived growth factor receptor) and soluble enzymes (e.g. Raf-1, Akt).2 Secondary to affecting Hsp90’s conformation and association with these client proteins, GA stimulates their proteasome-mediated degradation.3,4 Thus, although the molecular target of GA and its biologically active congeners is specific (Hsp90), the biologic effects of these drugs at the cellular level are, nevertheless, pleiotypic, in as much as multiple Hsp90 client proteins, many of them kinases, are destabilized. Because of its novel molecular target, and because GA has shown anti-tumor activity in animal models,5 a benzoquinone ansamycin has recently entered phase I clinical trial in five institutions worldwide. Because Hsp90 antagonism affects multiple signaling pathways, the fear has arisen that GA may be unacceptably toxic in vivo, although currently accumulating clinical data suggest that this concern may be overemphasized. HER-2 (p185c-ErbB2) is a receptor protein tyrosine kinase which is frequently overexpressed in a variety of human epithelial malignancies, and its overexpression has been associated with a poor clinical prognosis.6 Antibodies against HER-2 have been shown to have anti-tumor effects in animal models,7 and an anti-HER-2 antibody is being used clinically with some success.6,8 However, beneficial effects have been seen in a minority of treated patients, and clinical benefit has generally been of short duration. Because the therapeutic rationale for inhibiting HER-2 expression is strong, other nonantibody-based approaches are being examined. HER-2 is one of the most sensitive kinases with respect to GA-induced destabilization. In tissue culture experiments, 50% of total HER-2 protein is lost from HER-2-overexpressing SKBR3 cells within 90 min of drug exposure and complete loss of detectable protein occurs within several hours.4,9 If GA could somehow be specifically targeted to HER-2/Hsp90 complexes, it would represent a significant addition to the armamentarium of HER-2 inhibitors. One recent report has
described the covalent coupling of a GA derivative to the anti-HER-2 antibody Herceptin, and the finding that the antitumor activity of the conjugate was greater than that of Herceptin alone.10 Another recent approach at targeting GA to HER-2 has involved modifying the structure of GA itself in an attempt to alter its specificity.11 Both crystal structure analysis of GA bound to an amino terminal fragment of Hsp90 and structure-activity biochemical analysis of the Hsp90 binding ability of a large series of GA congeners suggest that the 17-carbon atom on the quinone ring of GA remains accessible once GA binds to the chaperone.12,13 Indeed, the benzoquinone ansamycin now in phase I clinical trial, 17-allylamino-GA, is modified by an alkyl side chain at the 17-carbon position in order to increase its stability and decrease its toxicity in vivo. 17-Allylamino-GA retains the Hsp90 inhibitory properties of GA.14 In an attempt to make GA more selective for HER-2 tyrosine kinase, Zheng et al. have recently described the synthesis and activity of a series of GA dimers with differing linker lengths.11 These dimers are covalently joined via linkage of their 17-carbon atoms. Zheng et al. have tested these GA dimers for Hsp90 target specificity and growth inhibitory activity in two breast-cancer-derived cell lines, MCF7 and SKBR3, as well as the hematopoietic cell line, 32D. Surprisingly, a GA dimer with a 4-carbon linker was found to retain the ability to destabilize HER-2 with comparable efficiency to GA, while it was more than 10-fold less effective than GA in destabilizing Raf-1. Other Hsp90 clients, including the estrogen receptor and the insulin-like growth factor receptor, were also less sensitive to the GA dimer, while other HER family members were destabilized as effectively as with GA. Neither GA nor the GA dimer affected HER-2 synthesis, but both drugs appeared to stimulate the transient accumulation of an incompletely glycosylated unstable form of the kinase. Mature HER-2 was rapidly lost from cells as well. Although the HER-2 destabilizing effect of GA and the GA dimer is thought to be secondary to interference with Hsp90, direct evidence for Hsp90 association with HER-2 is lacking, as is direct proof that GA-induced, and GA-dimerinduced, HER-2 instability is mediated via disruption of Hsp90 association. Nonetheless, Zheng et al.’s evidence that the GA dimer displays some selectivity for HER-2, compared to other GA targets, is compelling.The apparent selectivity of the GA dimer for the HER family implicates a novel sensitization pathway that, while involving Hsp90, is not common to the other GA targets examined. Two possibilities raised by Zheng et al. are (a) preferential interaction of the GA dimer with HER-2 dimers, and (b) preferential interaction of the GA dimer with another Hsp90 family member.The second possibility is unlikely, since only three Hsp90 family members have been described (Hsp90, Grp94, Trap-1) and GA binds with similar affinity to all of them.15 In addition, Trap-1 is localized to mitochondria and is unlikely to associate with plasma-membrane proteins.16 Grp94 is more interesting in that it is the endoplasmic reticulum (ER) homolog of Hsp90 and has been found in association with newly synthesized HER-2.9 While interference in its function might explain GA and GA dimer effects on nascent HER-2 proteins being processed in the ER, Grp94 is unlikely to mediate the ã 2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 203–205 doi: 10.1054/drup.2000.0149, available online at http://www.idealibrary.com on
203
Neckers
Fig. 1 Comparison of possible mechanisms for GA-induced and GA dimer-induced downregulation of HER-2. Scheme I (I): GA disrupts Hsp90 association with HER-2, resulting in HER-2 internalization (non-vesicular), ubiquitination and subsequent degradation by the proteasome. Scheme II (II): GA dimers temporarily ‘cross-link’ 2 HER-2 monomers by simultaneously binding the Hsp90 molecule associated with each HER-2 monomer.This permits HER-2 cross-phosphorylation (● ● ) and internalization in vesicles. Cytoplasmic tails of phosphorylated HER-2 are subsequently ubiquitinated and targeted to the proteasome for degradation.
extreme sensitivity of plasma membrane-localized HER-2 proteins to GA and the GA dimer, since the chaperone binds to a HER-2 domain which becomes extracellular upon insertion of the kinase in the plasma membrane (and Grp94 is a resident ER protein). This leaves Hsp90, the cytoplasmic member of the family, as the most likely target of these drugs in the context of HER-2 destabilization. The first possibility proposed by Zheng et al., that the GA dimer preferentially interacts with HER-2 dimers at the plasma membrane, is intriguing since HER receptor dimerization is common and cross-phosphorylation in response to ligand binding is required for receptor internalization and degradation (Fig. 1).17,18 It is possible that the GA dimer, by internally linking together 2 HER-2 monomers via their associated Hsp90 molecules, mimics ligand- or antibody-induced HER dimerization and triggers receptor internalization and degradation.The length of the linker arm in the most active GA dimer might fortuitously position the dimer to readily bind both members of a HER-2 dimer, bringing them close enough to phosphorylate each other.This hypothesis is readily testable, since the molecular requirements for GA-induced and ligand- or antibody-induced HER-2 downregulation are distinct and separable.19 A third alternative that might explain the results of Zheng et al. is that GA dimers which show specificity for HER-2 exert their effects by binding directly to the kinase. Previous reports have described direct interaction of benzoquinone ansamycins with tyrosine kinases, although at significantly higher drug concentrations than are necessary to specifically 204
Drug Resistance Updates (2000) 3, 203–205
ã 2000 Harcourt Publishers Ltd
bind Hsp90 and downregulate HER-2 expression.20,21 It is possible that the altered topography presented by a GA dimer with a 4-carbon linker arm dramatically improves affinity for HER-2 itself. However, such direct binding of ansamycin to HER-2 would have to trigger kinase destabilization and this has never been demonstrated. Until Hsp90 binding to a distinct domain on HER-2 can be clearly demonstrated, and until the effects of GA dimers on such binding can be directly observed, the correct explanation for the apparent specificity of GA dimers toward HER-2 will remain in doubt.These data raise additional unresolved questions. Why does the 4-carbon linked dimer have such a poor ability to destabilize Raf while the 7-carbon linked dimer is nearly as efficient as GA in this regard (and as efficient as the 4-carbon linked dimer in destabilizing HER-2)? Do the dimers with their various linker arm lengths bind with equal affinities to Hsp90? Why do the growth inhibitory activities of the various dimers toward HER-2-overexpressing SKBR3 cells not parallel their activities toward HER-2? For example, the 4-carbon linked GA dimer is only slightly less potent than GA at destabilizing HER-2 (60 nM vs. 45 nM IC50 respectively), while it is seven-fold less active in inhibiting the growth of SKBR3 cells.The 7-carbon linked GA dimer is as active towards HER-2 as is the 4-carbon linked GA dimer (70 nM vs. 60 nM IC50 respectively), but the 7-carbon linked dimer is 10-fold less potent than the 4-carbon linked GA dimer (and nearly 70-fold less potent than GA) in inhibiting the growth of SKBR3. Does this mean that destabilization of HER-2 is not the primary phenomenon mediating growth
Geldanamycin and Her-2 inhibition inhibition produced by GA in HER-2 overexpressing cells? Clearly, much remains to be learned in the experimental and ultimately clinical development of Hsp90 inhibitors,22 but the study by Zheng et al. emphasizes the potential of these reagents as possibly specific kinase destabilizing drugs.
Received 12 June 2000; Accepted 30 June 2000 Correspondence to: Leonard M. Neckers PhD, Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, 9610 Medical Center
9. 10.
11.
12.
Drive, Suite 300, Rockville, MD 20850, USA.Tel. +1 301 402 3128; x318; Fax: +1 301 402 4422; E-mail: [email protected]
13.
14. References 1. Whitesell L, Mimnaugh EG, DeCosta B et al. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 1994; 91: 8324–8328. 2. Neckers L, Mimnaugh EG, Schulte TW.The Hsp90 chaperone family. Handbook of Experimental Pharmacology 1999; 136: 9–42. 3. Schneider C, Sepp-Lorenzino L, Nimmersgen E et al. Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc Natl Acad Sci USA 1996; 93: 14536–14541. 4. Mimnaugh EG, Chavany C, Neckers LM. Polyubiquitination and proteasomal degradation of the p185c-erbB2 receptor protein tyrosine kinase induced by geldanamycin. J Biol Chem 1996; 271: 22796–22801. 5. Schnur RC, Corman ML, Gallaschun RJ et al. Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. J Med Chem 1995; 38: 3806–3812. 6. Ross JS, Fletcher JA.The HER-2/neu oncogene in breast cancer:prognostic factor, predictive factor and target for therapy. Stem Cells 1998; 16: 413–428. 7. Fan Z, Mendelsohn J.Therapeutic applications of anti-growth factor receptor antibodies. Curr Opin Oncol 1998; 10: 67–73. 8. Pegram MD, Lipton A, Hayes DF et al. Phase II study of receptorenhanced chemosensitivity using recombinant humanized p185HER2/neu monoclonal antibody plus cisplatin in patients with
15.
16.
17.
18.
19.
20.
21.
22.
HER2/neu-over-expressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2659–2671. Chavany C, Mimnaugh EG, Miller P et al. p185erbB2 binds to Grp94 in vivo. J Biol Chem 1996; 271: 4974–4977. Mandler R, Dadachova E, Brechbiel JK et al. Synthesis and evaluation of antiproliferative activity of a geldanamycin-Herceptin immunoconjugate. Bioorg Med Chem Lett 2000; 10: 1025–1028. Zheng FF, Kuduk SD, Chiosis G et al. Identification of a geldanamycin dimer that induces the selective degradation of HERfamily tyrosine kinases. Cancer Res 2000; 60: 2090–2094. Stebbins CE, Russo AA, Schneider C et al. Crystal structure of an Hsp90:geldanamycin complex – targeting of a protein chaperone by an anti-tumor agent. Cell 1997; 89: 239–250. Grenert JP, Sullivan WP, Fadden P et al.The amino terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 1997; 272: 23843–23850. Schulte TW, Neckers LM.The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to Hsp90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 1998; 42: 273–279. Schulte TW,Akinaga S, Murakata T et al. Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones. Mol Endocrinol 1999; 13: 1435–1448. Felts SJ, Owen BA, Nguyen P et al.The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 2000; 275: 3305–3312. Levkowitz G,Waterman H, Ettenberg SA et al. Ubiquitin ligase activity and tyrosine phosphorylation suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999; 4: 1029–1040. Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999; 19: 6845–6857. Xu W, Mimnaugh EG, Neckers LM. Sensitivity of ErbB2 to geldanamycin is conferred by its kinase domain. Submitted for publication. Fukazawa H, Uehara Y, Murakami Y et al. Labeling of v-Src and BCR-ABL tyrosine kinases with [14C]herbimycin A and its use in the elucidation of the kinase inactivation mechanism. FEBS Lett 1994; 340: 155–158. Hartmann F, Horak EM, Cho C et al. Effects of the tyrosine kinase inhibitor geldanamycin on ligand-induced Her-1/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines. Int J Cancer 1997; 70: 221–229. Neckers L, Mimnaugh E, Schulte TW. Hsp90 as an anti-cancer target. Drug Resistance Updates 1999; 2: 165–172.
ã 2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 203–205
205
Can the heat shock protein 90 inhibitor geldanamycin be designed to specifically inhibit HER-2 tyrosine kinase? Leonard M. Neckers Department of cell and Cancer Biology, National Cancer Institute, Rockville, USA
G
eldanamycin (GA), a member of the benzoquinone ansamycin class of antibiotics, is known to bind to and specifically inhibit the molecular chaperone heat shock protein 90 (Hsp90).1 Hsp90 is a very abundant cellular constituent which, among other functions, serves to stabilize and support the activity of a number of tyrosine and serine/threonine kinases, including transmembrane receptors (e.g. HER-1, HER-2, insulin-like growth factor receptor, platelet-derived growth factor receptor) and soluble enzymes (e.g. Raf-1, Akt).2 Secondary to affecting Hsp90’s conformation and association with these client proteins, GA stimulates their proteasome-mediated degradation.3,4 Thus, although the molecular target of GA and its biologically active congeners is specific (Hsp90), the biologic effects of these drugs at the cellular level are, nevertheless, pleiotypic, in as much as multiple Hsp90 client proteins, many of them kinases, are destabilized. Because of its novel molecular target, and because GA has shown anti-tumor activity in animal models,5 a benzoquinone ansamycin has recently entered phase I clinical trial in five institutions worldwide. Because Hsp90 antagonism affects multiple signaling pathways, the fear has arisen that GA may be unacceptably toxic in vivo, although currently accumulating clinical data suggest that this concern may be overemphasized. HER-2 (p185c-ErbB2) is a receptor protein tyrosine kinase which is frequently overexpressed in a variety of human epithelial malignancies, and its overexpression has been associated with a poor clinical prognosis.6 Antibodies against HER-2 have been shown to have anti-tumor effects in animal models,7 and an anti-HER-2 antibody is being used clinically with some success.6,8 However, beneficial effects have been seen in a minority of treated patients, and clinical benefit has generally been of short duration. Because the therapeutic rationale for inhibiting HER-2 expression is strong, other nonantibody-based approaches are being examined. HER-2 is one of the most sensitive kinases with respect to GA-induced destabilization. In tissue culture experiments, 50% of total HER-2 protein is lost from HER-2-overexpressing SKBR3 cells within 90 min of drug exposure and complete loss of detectable protein occurs within several hours.4,9 If GA could somehow be specifically targeted to HER-2/Hsp90 complexes, it would represent a significant addition to the armamentarium of HER-2 inhibitors. One recent report has
described the covalent coupling of a GA derivative to the anti-HER-2 antibody Herceptin, and the finding that the antitumor activity of the conjugate was greater than that of Herceptin alone.10 Another recent approach at targeting GA to HER-2 has involved modifying the structure of GA itself in an attempt to alter its specificity.11 Both crystal structure analysis of GA bound to an amino terminal fragment of Hsp90 and structure-activity biochemical analysis of the Hsp90 binding ability of a large series of GA congeners suggest that the 17-carbon atom on the quinone ring of GA remains accessible once GA binds to the chaperone.12,13 Indeed, the benzoquinone ansamycin now in phase I clinical trial, 17-allylamino-GA, is modified by an alkyl side chain at the 17-carbon position in order to increase its stability and decrease its toxicity in vivo. 17-Allylamino-GA retains the Hsp90 inhibitory properties of GA.14 In an attempt to make GA more selective for HER-2 tyrosine kinase, Zheng et al. have recently described the synthesis and activity of a series of GA dimers with differing linker lengths.11 These dimers are covalently joined via linkage of their 17-carbon atoms. Zheng et al. have tested these GA dimers for Hsp90 target specificity and growth inhibitory activity in two breast-cancer-derived cell lines, MCF7 and SKBR3, as well as the hematopoietic cell line, 32D. Surprisingly, a GA dimer with a 4-carbon linker was found to retain the ability to destabilize HER-2 with comparable efficiency to GA, while it was more than 10-fold less effective than GA in destabilizing Raf-1. Other Hsp90 clients, including the estrogen receptor and the insulin-like growth factor receptor, were also less sensitive to the GA dimer, while other HER family members were destabilized as effectively as with GA. Neither GA nor the GA dimer affected HER-2 synthesis, but both drugs appeared to stimulate the transient accumulation of an incompletely glycosylated unstable form of the kinase. Mature HER-2 was rapidly lost from cells as well. Although the HER-2 destabilizing effect of GA and the GA dimer is thought to be secondary to interference with Hsp90, direct evidence for Hsp90 association with HER-2 is lacking, as is direct proof that GA-induced, and GA-dimerinduced, HER-2 instability is mediated via disruption of Hsp90 association. Nonetheless, Zheng et al.’s evidence that the GA dimer displays some selectivity for HER-2, compared to other GA targets, is compelling.The apparent selectivity of the GA dimer for the HER family implicates a novel sensitization pathway that, while involving Hsp90, is not common to the other GA targets examined. Two possibilities raised by Zheng et al. are (a) preferential interaction of the GA dimer with HER-2 dimers, and (b) preferential interaction of the GA dimer with another Hsp90 family member.The second possibility is unlikely, since only three Hsp90 family members have been described (Hsp90, Grp94, Trap-1) and GA binds with similar affinity to all of them.15 In addition, Trap-1 is localized to mitochondria and is unlikely to associate with plasma-membrane proteins.16 Grp94 is more interesting in that it is the endoplasmic reticulum (ER) homolog of Hsp90 and has been found in association with newly synthesized HER-2.9 While interference in its function might explain GA and GA dimer effects on nascent HER-2 proteins being processed in the ER, Grp94 is unlikely to mediate the ã 2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 203–205 doi: 10.1054/drup.2000.0149, available online at http://www.idealibrary.com on
203
Neckers
Fig. 1 Comparison of possible mechanisms for GA-induced and GA dimer-induced downregulation of HER-2. Scheme I (I): GA disrupts Hsp90 association with HER-2, resulting in HER-2 internalization (non-vesicular), ubiquitination and subsequent degradation by the proteasome. Scheme II (II): GA dimers temporarily ‘cross-link’ 2 HER-2 monomers by simultaneously binding the Hsp90 molecule associated with each HER-2 monomer.This permits HER-2 cross-phosphorylation (● ● ) and internalization in vesicles. Cytoplasmic tails of phosphorylated HER-2 are subsequently ubiquitinated and targeted to the proteasome for degradation.
extreme sensitivity of plasma membrane-localized HER-2 proteins to GA and the GA dimer, since the chaperone binds to a HER-2 domain which becomes extracellular upon insertion of the kinase in the plasma membrane (and Grp94 is a resident ER protein). This leaves Hsp90, the cytoplasmic member of the family, as the most likely target of these drugs in the context of HER-2 destabilization. The first possibility proposed by Zheng et al., that the GA dimer preferentially interacts with HER-2 dimers at the plasma membrane, is intriguing since HER receptor dimerization is common and cross-phosphorylation in response to ligand binding is required for receptor internalization and degradation (Fig. 1).17,18 It is possible that the GA dimer, by internally linking together 2 HER-2 monomers via their associated Hsp90 molecules, mimics ligand- or antibody-induced HER dimerization and triggers receptor internalization and degradation.The length of the linker arm in the most active GA dimer might fortuitously position the dimer to readily bind both members of a HER-2 dimer, bringing them close enough to phosphorylate each other.This hypothesis is readily testable, since the molecular requirements for GA-induced and ligand- or antibody-induced HER-2 downregulation are distinct and separable.19 A third alternative that might explain the results of Zheng et al. is that GA dimers which show specificity for HER-2 exert their effects by binding directly to the kinase. Previous reports have described direct interaction of benzoquinone ansamycins with tyrosine kinases, although at significantly higher drug concentrations than are necessary to specifically 204
Drug Resistance Updates (2000) 3, 203–205
ã 2000 Harcourt Publishers Ltd
bind Hsp90 and downregulate HER-2 expression.20,21 It is possible that the altered topography presented by a GA dimer with a 4-carbon linker arm dramatically improves affinity for HER-2 itself. However, such direct binding of ansamycin to HER-2 would have to trigger kinase destabilization and this has never been demonstrated. Until Hsp90 binding to a distinct domain on HER-2 can be clearly demonstrated, and until the effects of GA dimers on such binding can be directly observed, the correct explanation for the apparent specificity of GA dimers toward HER-2 will remain in doubt.These data raise additional unresolved questions. Why does the 4-carbon linked dimer have such a poor ability to destabilize Raf while the 7-carbon linked dimer is nearly as efficient as GA in this regard (and as efficient as the 4-carbon linked dimer in destabilizing HER-2)? Do the dimers with their various linker arm lengths bind with equal affinities to Hsp90? Why do the growth inhibitory activities of the various dimers toward HER-2-overexpressing SKBR3 cells not parallel their activities toward HER-2? For example, the 4-carbon linked GA dimer is only slightly less potent than GA at destabilizing HER-2 (60 nM vs. 45 nM IC50 respectively), while it is seven-fold less active in inhibiting the growth of SKBR3 cells.The 7-carbon linked GA dimer is as active towards HER-2 as is the 4-carbon linked GA dimer (70 nM vs. 60 nM IC50 respectively), but the 7-carbon linked dimer is 10-fold less potent than the 4-carbon linked GA dimer (and nearly 70-fold less potent than GA) in inhibiting the growth of SKBR3. Does this mean that destabilization of HER-2 is not the primary phenomenon mediating growth
Geldanamycin and Her-2 inhibition inhibition produced by GA in HER-2 overexpressing cells? Clearly, much remains to be learned in the experimental and ultimately clinical development of Hsp90 inhibitors,22 but the study by Zheng et al. emphasizes the potential of these reagents as possibly specific kinase destabilizing drugs.
Received 12 June 2000; Accepted 30 June 2000 Correspondence to: Leonard M. Neckers PhD, Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, 9610 Medical Center
9. 10.
11.
12.
Drive, Suite 300, Rockville, MD 20850, USA.Tel. +1 301 402 3128; x318; Fax: +1 301 402 4422; E-mail: [email protected]
13.
14. References 1. Whitesell L, Mimnaugh EG, DeCosta B et al. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 1994; 91: 8324–8328. 2. Neckers L, Mimnaugh EG, Schulte TW.The Hsp90 chaperone family. Handbook of Experimental Pharmacology 1999; 136: 9–42. 3. Schneider C, Sepp-Lorenzino L, Nimmersgen E et al. Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc Natl Acad Sci USA 1996; 93: 14536–14541. 4. Mimnaugh EG, Chavany C, Neckers LM. Polyubiquitination and proteasomal degradation of the p185c-erbB2 receptor protein tyrosine kinase induced by geldanamycin. J Biol Chem 1996; 271: 22796–22801. 5. Schnur RC, Corman ML, Gallaschun RJ et al. Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. J Med Chem 1995; 38: 3806–3812. 6. Ross JS, Fletcher JA.The HER-2/neu oncogene in breast cancer:prognostic factor, predictive factor and target for therapy. Stem Cells 1998; 16: 413–428. 7. Fan Z, Mendelsohn J.Therapeutic applications of anti-growth factor receptor antibodies. Curr Opin Oncol 1998; 10: 67–73. 8. Pegram MD, Lipton A, Hayes DF et al. Phase II study of receptorenhanced chemosensitivity using recombinant humanized p185HER2/neu monoclonal antibody plus cisplatin in patients with
15.
16.
17.
18.
19.
20.
21.
22.
HER2/neu-over-expressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2659–2671. Chavany C, Mimnaugh EG, Miller P et al. p185erbB2 binds to Grp94 in vivo. J Biol Chem 1996; 271: 4974–4977. Mandler R, Dadachova E, Brechbiel JK et al. Synthesis and evaluation of antiproliferative activity of a geldanamycin-Herceptin immunoconjugate. Bioorg Med Chem Lett 2000; 10: 1025–1028. Zheng FF, Kuduk SD, Chiosis G et al. Identification of a geldanamycin dimer that induces the selective degradation of HERfamily tyrosine kinases. Cancer Res 2000; 60: 2090–2094. Stebbins CE, Russo AA, Schneider C et al. Crystal structure of an Hsp90:geldanamycin complex – targeting of a protein chaperone by an anti-tumor agent. Cell 1997; 89: 239–250. Grenert JP, Sullivan WP, Fadden P et al.The amino terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 1997; 272: 23843–23850. Schulte TW, Neckers LM.The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to Hsp90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 1998; 42: 273–279. Schulte TW,Akinaga S, Murakata T et al. Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones. Mol Endocrinol 1999; 13: 1435–1448. Felts SJ, Owen BA, Nguyen P et al.The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 2000; 275: 3305–3312. Levkowitz G,Waterman H, Ettenberg SA et al. Ubiquitin ligase activity and tyrosine phosphorylation suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999; 4: 1029–1040. Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999; 19: 6845–6857. Xu W, Mimnaugh EG, Neckers LM. Sensitivity of ErbB2 to geldanamycin is conferred by its kinase domain. Submitted for publication. Fukazawa H, Uehara Y, Murakami Y et al. Labeling of v-Src and BCR-ABL tyrosine kinases with [14C]herbimycin A and its use in the elucidation of the kinase inactivation mechanism. FEBS Lett 1994; 340: 155–158. Hartmann F, Horak EM, Cho C et al. Effects of the tyrosine kinase inhibitor geldanamycin on ligand-induced Her-1/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines. Int J Cancer 1997; 70: 221–229. Neckers L, Mimnaugh E, Schulte TW. Hsp90 as an anti-cancer target. Drug Resistance Updates 1999; 2: 165–172.
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