Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models.
Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.
Caldas-Lopes
Eloisi
E
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cerchietti
Leandro
L
Ahn
James H
JH
Clement
Cristina C
CC
Robles
Ana I
AI
Rodina
Anna
A
Moulick
Kamalika
K
Taldone
Tony
T
Gozman
Alexander
A
Guo
Yunke
Y
Wu
Nian
N
de Stanchina
Elisa
E
White
Julie
J
Gross
Steven S
SS
Ma
Yuliang
Y
Varticovski
Lyuba
L
Melnick
Ari
A
Chiosis
Gabriela
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency; D011960:Receptors, Estrogen / Q000172:deficiency; D011980:Receptors, Progesterone / Q000172:deficiency; D012074:Remission Induction
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-