Reference Detail

Ref Type
PMID (27706135)
Authors Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G
Title The epichaperome is an integrated chaperome network that facilitates tumour survival.
Journal Nature
Vol 538
Issue 7625
Date 2016 Oct 05
URL
Abstract Text Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown stomach cancer not applicable PU-H71 Preclinical - Cell culture Actionable In a preclinical study, sensitivity to PU-H71 was correlated to presence of the epichaperome, a network of chaperome complexes, in gastric cancer cell lines in culture (PMID: 27706135). 27706135
Unknown unknown lung cancer not applicable PU-H71 Preclinical - Cell culture Actionable In a preclinical study, sensitivity to PU-H71 was correlated to presence of the epichaperome, a network of chaperome complexes, in lung cancer cell lines in culture (PMID: 27706135). 27706135
Unknown unknown lymphoma not applicable PU-H71 Preclinical - Cell culture Actionable In a preclinical study, sensitivity to PU-H71 was correlated to presence of the epichaperome, a network of chaperome complexes, in lymphoma cell lines in culture (PMID: 27706135). 27706135
Unknown unknown breast cancer not applicable PU-H71 Preclinical - Cell culture Actionable In a preclinical study, sensitivity to PU-H71 was correlated to presence of the epichaperome, a network of chaperome complexes, in breast cancer cell lines in culture (PMID: 27706135). 27706135