BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.
17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis.
Zhang
Hong
H
Biogen Idec, 5200 Research Place, San Diego, CA, USA. Hong.zhang@biogenidec.com
Neely
Laura
L
Lundgren
Karen
K
Yang
Yong-Ching
YC
Lough
Rachel
R
Timple
Noel
N
Burrows
Francis
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000225:Adenine; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; C112765:tanespimycin; C421109:multidrug resistance-associated protein 1