The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

Park, Kang-Seo; Oh, Byung Hak; Lee, Mi-Hee; Nam, Ky-Youb; Jin, Hae Ran; Yang, Hannah; Choi, Joon Ho; Lee, Dong Hoon

doi:10.1016/j.canlet.2015.12.015

Cited by 35 publications

(24 citation statements)

References 39 publications

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“…AUY922 is a second‐generation synthetic HSP90 inhibitor that can influence many HSP90 client proteins. It can inhibit phosphorylation status of ErbB receptor proteins and PI3K/AKT, ERK pathway proteins alone after 24 h treatment in our results, this is in line with the results also in lung cancer . It is an inhibitor that can target more than only one signal pathway, which benefits it more efficiency in tumor inhibition.…”

Section: Discussionsupporting

confidence: 90%

“…It can inhibit phosphorylation status of ErbB receptor proteins and PI3K/AKT, ERK pathway proteins alone after 24 h treatment in our results, this is in line with the results also in lung cancer. (18) It is an inhibitor that can target more than only one signal pathway, which benefits it more efficiency in tumor inhibition. In other papers, it showed that inhibition of HER-2 alone had no effect on the HER-2 over expressing T47D fulvestrant resistant cell lines, (19) which suggests that single inhibition of one target may not be enough.…”

Section: Discussionmentioning

confidence: 99%

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HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells

et al. 2017

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Hormone therapy has become one of the main strategies for breast cancer, however, many estrogen receptor (ER) positive patients end in tumor collapse due to initial or acquired resistance to hormone treatment, which includes Fulvestrant. Here we report that ErbB receptors and downstream PI3K/AKT and ERK pathway have been reactivated after treatment of Fulvestrant in ER positive MCF‐7 and T47D cells, which are related to Fulvestrant resistance. HSP90 is a universally expressed chaperone protein and plays a vital role in both normal and cancer cells, HSP90 inhibitor AUY922 can reverse this feedback reactivation effect of Fulvestrant by targeting multiple proteins related in ErbB receptors, PI3K/AKT and ERK pathway, which is much better than single targeting inhibitors. We also consolidate these effects in human fresh breast tumors. Combination of AUY922 and Fulvestrant may become a promising therapy strategy in breast cancer treatment.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells

et al. 2017

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“…For example, in response to MEK inhibition, PI3K is activated through a negative MEK-epidermal growth factor receptor-PI3K feedback loop 32,112 . Therefore, novel therapeutic approaches are focusing on the disruption of these multiple nodes, which is only possible through the inhibition of multiple downstream kinases, rather than only one through combination therapy 100-104 ( Table 4 ).…”

Section: Rna Interferencementioning

confidence: 99%

“…The complexity of KRAS signaling pathways, in which KRAS protein interacts with many different upstream mediators, downstream effectors, and transcription factors in a nonlinear fashion, has a critical role in the lack of effective treatment 32-34 . Thus, a better understanding of KRAS interactions with other proteins and transcription factors may provide new opportunities for effective treatment ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

2019

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Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRASonc) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.

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“…A number of HSP90 inhibitors have entered pre‐clinical and clinical studies . Of note, oncogene‐driven cancer cells, including mutant KRAS colon cancer cells, are susceptible to HSP90 inhibition . However, only transient responses to HSP90 inhibitors have been observed in patients with mutant KRAS tumors .…”

Section: Introductionmentioning

confidence: 99%

BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

Wang

Guo

Croft

et al. 2017

Molecular Carcinogenesis

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Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer.

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The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

Cited by 35 publications

References 39 publications

HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells

HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

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