Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

Tanno, Satoshi; Yanagawa, Nobuyuki; Habiro, Atsuya; Koizumi, Kazuya; Nakano, Yasuhiro; Osanai, Manabu; Mizukami, Yusuke; Okumura, Toshikatsu; Testa, Joseph R.; Kohgo, Yutaka

doi:10.1158/0008-5472.can-03-1788

Cited by 98 publications

(77 citation statements)

References 36 publications

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“…26,27 We have previously described a novel intraperitoneally administered, ansamycinbased Hsp90 inhibitor, EC5, which effectively inhibited the growth of HNSCC cells in vitro and in in vivo tumor models. 13 Several Hsp90 client proteins including EGFR, ErbB2, Raf-1, vascular epithelial growth factor (VEGF) and protein kinase B (PKB0/Akt) are known to play a role in radiation resistance, [22][23][24] and this positions Hsp90 inhibitors as good candidates for therapeutic radiosensitization.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] Furthermore, the reduction of either total proteins or their active/ phosphorylated form has been used as biomarkers of Hsp90 inhibition. 9 To explore the degradation of these key client proteins, western blot analysis was performed on extracts of JHU12 and UM11B cells following 24 hr exposure to either 1 lM BIIB021 or 5 Gy radiation alone, or in combination.…”

Section: Biib021 Inhibited Hsp90 Key Client Protein Expression and Acmentioning

confidence: 99%

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BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

Yin

Zhang

Lundgren

et al. 2009

Intl Journal of Cancer

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Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical testing. However, 17-AAG is difficult to formulate and associated with dose-limited toxicity issues. A fully synthetic and bioavailable Hsp90 inhibitor, BIIB021, was evaluated for antitumor activity in a variety of head and neck squamous cell carcinoma (HNSCC) cell lines and HNSCC xenograft models, either as a single agent or in combination with fractionated radiation and the results were compared with that of 17-AAG. BIIB021 showed strong antitumor activity, comparable with, and in certain instances, superior to 17-AAG. BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. In xenograft studies, BIIB021 exhibited a strong antitumor effect outperforming 17-AAG, either as a single agent and or in combination with radiation, thereby improved the efficacy of radiation. These results suggest that this synthetic and bioavailable Hsp90 inhibitor affects multiple pathways involved in tumor development and progression in the HNSCC setting and may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or a radiosensitizer. Furthermore, it also demonstrates the benefits of using preclinical models of chemosensitization to radiotherapy to explore clinically relevant radiation dosing schemes.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with approximately 600,000 new cases reported each year. More than 50% of newly diagnosed patients will eventually relapse with either local recurrence or distant metastases. Unfortunately, in the relapse setting prognosis is poor, with median overall survival limited to about 1 year. Current treatment paradigms depend upon the stage of the disease at presentation. The standard treatment for loco-regional disease involves surgery and/or radiotherapy in either the neo-or adjuvant setting. Radiotherapy almost always employed with locally advanced disease, with a variety of fractionation regimens currently in clinical practice. Efforts to increase the efficacy of radiotherapy have included combination with chemotherapy, initially in the concomitant setting with platinum-containing regimens (chemoradiotherapy) and most recently as adjuvant treatment. [1][2][3] Although the locoregional control and survival rates associated with chemoradiotherapy are higher than those for radiation alone, these intensive regimens are frequently associated with severe toxicities, leading to significant comorbidities. Targeted biological therapies that selectively interfere with cancer cell growth signals may improve patient survival by enhancing the effects of radiation, with the added b...

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Section: Discussionmentioning

confidence: 99%

Section: Biib021 Inhibited Hsp90 Key Client Protein Expression and Acmentioning

confidence: 99%

BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

Yin

Zhang

Lundgren

et al. 2009

Intl Journal of Cancer

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“…The EGFR signaling pathway is integral in epithelial cell growth and proliferation, where preclinical studies have shown tumor regression with EGFR inhibition (28,30), forming the rationale for targeting EGFR for treatment. While initial small studies demonstrated promising antitumor activity with anti-EGFR therapy in combination with gemcitabine-based chemotherapy (31,32), these findings were unable to translate into a significant clinical benefit in larger randomized clinical trials (33,34 (35,36).…”

Section: Egfr Signaling Pathwaymentioning

confidence: 99%

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

Ahn

Bekaii‐Saab

2017

J. Gastrointest. Oncol.

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Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify genes that are likely contributing to its pathogenesis, proliferation and treatment resistance. Additionally, these advances have allowed us to reason that each anatomic group within BC behave as distinct diseases, with differences in prognosis and outcomes. Based on this knowledge, recent advances have allowed us to identify actionable mutations that form rational therapeutic targets with novel agents, where their relevance will be better understood through the completion of prospective clinical trials.

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“…Among the client proteins of Hsp90 are steroid hormone receptors, Src family kinases, cyclin-dependent kinases (Cdk4 and 6), and the HIF-1a transcription factor (13). In addition, Hsp90 acts to stabilize Raf-1, Akt, and ErbB2 (14,15), each of which has been associated with protection against radiation-induced cell death; a reduction in their individual activities has been shown to result in radiosensitization in certain cell lines (16)(17)(18)(19) Consequently, inhibition of Hsp90 results in the simultaneous loss of multiple molecules that could affect radiosensitivity. Thus, Hsp90 inhibitors provide a strategy for implementing a multitarget approach to radiosensitization.…”

Section: Introductionmentioning

confidence: 99%

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

et al. 2005

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The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radiosensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensitivity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient. (Cancer Res 2005; 65(15): 6967-75)

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Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

Cited by 98 publications

References 36 publications

BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

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