JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma

Abstract

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. .

Applications of patient-derived tumor xenograft models and tumor organoids

“…PDXs often maintain the cellular and histopathological structures of the original tumors (Table 1) [7][8][9]. Furthermore, cytogenetic analysis of tumor cells from PDXs has revealed significant preservation of the genomic and gene expression profiles between PDXs and parental patient tumors [10][11][12][13][14]. Notably, sensitivity to standard chemotherapeutics in PDXs closely correlates with clinical data in patients from which the PDXs are derived [12,13,[15][16][17][18].…”

Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1

“…24 Recent reports proposed that JQ1, a selective inhibitor of BET proteins, exerts antigrowth effects in many types of cancer, inducing cell cycle arrest in cancer cells followed by the downregulation of the MYC oncogene. [25][26][27][28][29][30] However, the efficacy of JQ1 for BTC remains unknown. 30 In the present study, we investigated the therapeutic efficacy of JQ1 for ICC cells and identified the possible involvement of mutant IDH1 in the sensitivity to JQ1.…”

“…Bromodomain and extraterminal domain (BET) family proteins (BRD2, BRD3, BRD4, and BRDT) recognize acetylated lysine residues on histone tails and facilitate transcriptional activation through the recruitment of transcriptional regulatory complexes . Recent reports proposed that JQ1, a selective inhibitor of BET proteins, exerts antigrowth effects in many types of cancer, inducing cell cycle arrest in cancer cells followed by the downregulation of the MYC oncogene . However, the efficacy of JQ1 for BTC remains unknown .…”

Blocking the Bromodomains Function Contributes to Disturbances in Alga Chara vulgaris Spermatids Differentiation

“…Bromodomains participate in the spermatogenesis control system [42]. Studies of this process using bromodomain inhibitors i.e., highly specific JQ1, showed that it suppressed the expression of many genes that play essential roles in germ cells [24,43,44]. This inhibitor does not affect the proliferative properties of spermatogonia, but influences later stages of their development, spermatocytes and spermatids [37].…”