Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

Chen, Ming-Huang; Chiang, Kun Chun; Cheng, Chi‐Tung; Huang, Shih Chiang; Chen, Yeng Yang; Chen, Tsung Wen; Yeh, Ta Sen; Jan, Yi Yin; Wang, Hsi Ming; Weng, Jiang Jie; Chang, Peter Mu Hsin; Liu, Chun Yu; Li, Chung Pin; Chao, Yee; Huang, Chi Ying F.; Yeh, Chun‐Nan

doi:10.18632/oncotarget.1706

Cited by 63 publications

(49 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inhibition of mTOR signaling may prevent CSC self-renewal and circumvent CSC-mediated resistance to cancer therapeutics [23]. Previous studies have demonstrated that mTOR inhibitor, combined with other antitumor agents or not, could inhibit the development of CCA [28, 29, 34, 35]. ZEB1 silencing, either chemically or by RNAi, in mesenchymal-like cells results in a partial epithelial metaplasia and drug sensitivity [36, 37].…”

Section: Discussionmentioning

confidence: 99%

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

et al. 2015

View full text Add to dashboard Cite

Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.

show abstract

Section: Discussionmentioning

confidence: 99%

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…[22] In line with this, co-administration of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor, NVP-BEZ235, with HSP90 inhibitor, NVP-AUY922, synergistically increases apoptosis in both cholangiocarcinoma cells and thioacetamide-induced cholangiocarcinoma animal model. [23] Consistently, Saturno et al investigated the effect of HSP90 inhibitor on TNF-related apoptosis-inducing ligand (TRAIL) resistance in colorectal cancer. They showed that co-treatment of TRAIL with HSP90 inhibitor, 17-AAG, considerably increases apoptosis as compared with a single treatment group in TRAIL-resistant xenograft models of human colorectal cancer.…”

Section: Gastricmentioning

confidence: 99%

Therapeutic potency of heat-shock protein-90 pharmacological inhibitors in the treatment of gastrointestinal cancer, current status and perspectives

Boroumand

Saghi

Avan

et al. 2017

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives Heat-shock protein-90 (HSP90) chaperone machinery is critical to the folding, stability and activity of several client proteins including many responsible for tumour initiation, progression and metastasis. Overexpression of HSP90 is correlated with poor prognosis of GI cancer. Key findings Pharmacological inhibitors of HSP90 suppress tumorigenic effects of HSP90 by suppressing angiogenesis, survival, metastasis and drug resistance in GI cancer. This review summarizes the role of HSP90 inhibitors in the treatment of GI cancer. Summary We have presented different antitumour mechanisms of HSP90 inhibitors in cancer treatment. Suppression of HSP90 signalling via specific and novel pharmacological inhibitors is a potentially novel therapeutic approach for patients with GI cancer for a better understanding and hence a better management of this disease.

show abstract

“…Intrahepatic CCA, like most other human cancers, commonly shows increased activation of members of the AKT-PTEN-PI3KCA-mTOR pathway, an increase often caused by inactivation of PTEN [76][77][78] . Independent of PTEN expression, levels of phosphorylated AKT or mTOR have been suggested to be prognostic markers associated with good outcome in iCCA [79] .…”

Section: Downstream Of the Erbb Receptorsmentioning

confidence: 99%

“…Independent of PTEN expression, levels of phosphorylated AKT or mTOR have been suggested to be prognostic markers associated with good outcome in iCCA [79] . In fact, attempts to target this pathway either using a PI3K inhibitor (NVP-BEZ235) alone [76,77] or in combination with the selective HSP90 inhibitor (NVP-AUY922) [76] have demonstrated promising anticancer activity [77] as well as increased oxidative and ER stress [76] .…”

Section: Downstream Of the Erbb Receptorsmentioning

confidence: 99%

Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

Høgdall

O’Rourke

Taranta

et al. 2016

Dig Dis

View full text Add to dashboard Cite

Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome.

show abstract

Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

Cited by 63 publications

References 52 publications

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

Therapeutic potency of heat-shock protein-90 pharmacological inhibitors in the treatment of gastrointestinal cancer, current status and perspectives

Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

Contact Info

Product

Resources

About