Combination therapies with HSP90 inhibitors against colorectal cancer

Kryeziu, Kushtrim; Bruun, Jarle; Guren, Tormod Kyrre; Sveen, Anita; Lothe, Ragnhild

doi:10.1016/j.bbcan.2019.01.002

Cited by 85 publications

(85 citation statements)

References 68 publications

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“…Our global analysis and validation of the functional consequences of PPIN rewiring facilitates the rational design of combinatorial targeting of mtKRAS effectors, especially as PPIs gained in mtKRAS Hi cells inversely correlate with CRC patient survival. For instance, HSPs receive high IF in mtKRAS Hi cells, and HSP90 inhibitors recently were found to enhance the effects of conventional CRC drug therapies 52 . Likewise, our results that phosphorylation changes contribute to PPIN rewiring may "repurpose" kinase inhibitors as PPIN rewiring agents.…”

Section: Discussionmentioning

confidence: 99%

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

et al. 2020

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Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS G13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS G13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

et al. 2020

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“…Several HSP90 inhibitors are currently undergoing clinical trials as cancer therapies, both as monotherapy and in combination with common antineoplastic therapies or radiation therapy (17,18). HSP90 inhibitors mainly target the N-terminal ATPase on HSP90 and are able to displace ATP, blocking HSP90 function (11,19).…”

Section: Introductionmentioning

confidence: 99%

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

et al. 2020

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Rational: Cisplatin based cancer therapy is an affordable and effective standard therapy for several solid cancers, including lung, ovarian and head and neck cancers. However, the clinical use of cisplatin is routinely limited by the development of drug resistance and subsequent therapeutic failure. Therefore, methods of circumventing cisplatin resistance have the potential to increase therapeutic efficiency and dramatically increase overall survival. Cisplatin resistance can be mediated by alterations to the DNA damage response, where multiple components of the repair machinery have been described to be client proteins of HSP90. In the present study, we have investigated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and potentially reverse cisplatin resistance in ovarian and head and neck cancer cells. Methods: Cell viability, cancer cell proliferation and migration capacity were evaluated in vitro on models of ovarian and head and neck cancer cells. Western blotting was used to assess the downregulation of HSP90 client proteins and alterations in downstream signaling proteins after exposure to cisplatin and/or onalespib. Induction of apoptosis and DNA damage response were evaluated in both monotherapy and combination therapy groups. Results: Results demonstrate that onalespib enhances the efficiency of cisplatin in a dose-dependent manner. Tumor cells treated with both drugs displayed lower viability and a decreased migration rate compared to vehicle-control cells and cells treated with individual compounds. An increase of DNA double strand breaks was observed in both cisplatin and onalespib treated cells. The damage was highest and most persistent in the combination group, delaying the DNA repair machinery. Further, the cisplatin and onalespib co-treated cells had greater apoptotic activity compared to controls. Conclusion: The results of this study demonstrate that the reduced therapeutic efficacy of cisplatin due to drug-resistance could be overcome by combination treatment with onalespib. We speculate that the increased apoptotic signaling, DNA damage as well as the downregulation of HSP90 client proteins are important mechanisms promoting increased sensitivity to cisplatin treatment.

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“…Given that Hakai oncogene is also aberrantly highly expressed in colorectal cancer [10,13,20,43], and the demonstrated interaction between Hsp90 and Hakai in vitro, future investigations on the role of Hsp90 and Hakai in vivo await to be elucidated. Promoting the degradation of Hsp90 oncogenic client proteins by inhibiting Hsp90 is considered as a promising new anticancer strategy [44,45]. Since the appearance of the first generation Hsp90 inhibitors, such as geldanamycin and radicicol, many derivative compounds have been developed and studied for cancer treatment and subjected to clinical trials [29,46].…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

Díaz-Díaz

Roca-Lema

Casas-Pais

et al. 2020

Cancers

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The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90.

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Combination therapies with HSP90 inhibitors against colorectal cancer

Cited by 85 publications

References 68 publications

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

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