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.
|Number of pages||12|
|Journal||Molecular Cancer Therapeutics|
|State||Published - Jan 2018|
Bibliographical noteFunding Information:
The authors are indebted to the cholangiocarcinoma patients who agreed to participate in this study. This project was supported by NIH grant R21 CA205501, American Cancer Society-Institutional Research Grant (IRG-60-001-50), and UAB/UMN SPORE in pancreatic cancer (P50 CA101955). This project was supported by NIH grant R21 CA205501 (K.J. Yoon), American Cancer Society-Institutional Research Grant (IRG-60-001-50; K.J. Yoon), and UAB/UMN SPORE in pancreatic cancer pilot grant (P50 CA101955; K.J. Yoon).
© 2017 AACR.
ASJC Scopus subject areas
- Cancer Research