We reported previously that the BET inhibitor (BETi) JQ1 decreases levels of the DNA repair protein RAD51 and that this decrease is concomitant with increased levels of DNA damage. Based on these findings, we hypothesized that a BETi would augment DNA damage produced by radiation and function as a radiosensitizer. We used clonogenic assays to evaluate the effect of JQ1 ± ionizing radiation (IR) on three pancreatic cancer cell lines in vitro. We performed immunofluorescence assays to assess the impact of JQ1 ± IR on DNA damage as reflected by levels of the DNA damage marker γH2AX, and immunoblots to assess levels of the DNA repair protein RAD51. We also compared the effect of these agents on the clonogenic potential of transfectants that expressed contrasting levels of the principle molecular targets of JQ1 (BRD2, BRD4) to determine whether levels of these BET proteins affected sensitivity to JQ1 ± IR. The data show that JQ1 + IR decreased the clonogenic potential of pancreatic cancer cells more than either modality alone. This anticlonogenic effect was associated with increased DNA damage and decreased levels of RAD51. Further, lower levels of BRD2 or BRD4 increased sensitivity to JQ1 and JQ1 + IR, suggesting that pre-treatment levels of BRD2 or BRD4 may predict sensitivity to a BETi or to a BETi + IR. We suggest that a BETi + IR merits evaluation as therapy prior to surgery for pancreatic cancer patients with borderline resectable disease.
|Journal||Frontiers in Oncology|
|State||Published - Jun 20 2022|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (National Cancer Institute) grant R01CA208272 (KY). EY received grant support from Eli Lilly and PUMA Biotechnologies, Inc. that is unrelated to this study. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
Copyright © 2022 Garcia, Miller, Zeng, van Waardenburg, Yang and Yoon.
- BET inhibitor
- DNA damage repair
- pancreatic cancer
ASJC Scopus subject areas
- Cancer Research