TY - JOUR
T1 - JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma
AU - Garcia, Patrick L.
AU - Miller, Aubrey L.
AU - Gamblin, Tracy L.
AU - Council, Leona N.
AU - Christein, John D.
AU - Arnoletti, J. Pablo
AU - Heslin, Marty J.
AU - Reddy, Sushanth
AU - Richardson, Joseph H.
AU - Cui, Xiangqin
AU - Van Waardenburg, Robert C.A.M.
AU - Bradner, James E.
AU - Yang, Eddy S.
AU - Yoon, Karina J.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2018/1
Y1 - 2018/1
N2 - Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ∼8 months. Combining this agent with cisplatin increases survival by ∼3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.
AB - Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ∼8 months. Combining this agent with cisplatin increases survival by ∼3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.
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U2 - 10.1158/1535-7163.MCT-16-0922
DO - 10.1158/1535-7163.MCT-16-0922
M3 - Article
C2 - 29142067
AN - SCOPUS:85040089301
SN - 1535-7163
VL - 17
SP - 107
EP - 118
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -