Reference Detail

Ref Type Journal Article
PMID (26832792)
Authors Wang CY, Guo ST, Wang JY, Liu F, Zhang YY, Yari H, Yan XG, Jin L, Zhang XD, Jiang CC
Title Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress.
Journal Molecular cancer therapeutics
Vol 15
Issue 3
Date 2016 Mar
URL
Abstract Text Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
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
KRAS G12V colon cancer sensitive Luminespib Preclinical - Cell culture Actionable In a preclinical study, Luminespib (AUY922) inhibited growth of colon cancer cell lines harboring KRAS G12V in culture (PMID: 26832792). 26832792
KRAS G12D colon cancer sensitive Luminespib Preclinical - Cell culture Actionable In a preclinical study, Luminespib (AUY922) inhibited growth of a colon cancer cell line harboring KRAS G12D in culture (PMID: 26832792). 26832792
KRAS mutant colon cancer predicted - sensitive Luminespib Preclinical - Cell line xenograft Actionable In a preclinical study, colon cancer cell lines with KRAS codon 12 or 13 mutations demonstrated increased sensitivity to treatment with Luminespib (AUY922) in culture and in xenograft models (PMID: 26832792). 26832792
KRAS G13D colon cancer sensitive Luminespib Preclinical - Cell line xenograft Actionable In a preclinical study, a colon cancer cell line harboring KRAS G13D demonstrated increased sensitivity to Luminespib (AUY922) compared to cell lines with wild-type KRAS, resulting in decreased viability and increased apoptosis in culture and reduced tumor growth in xenograft models (PMID: 26832792). 26832792