TY - JOUR
T1 - Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription
AU - Cameron, Donald P.
AU - Grosser, Jan
AU - Ladigan, Swetlana
AU - Kuzin, Vladislav
AU - Iliopoulou, Evanthia
AU - Wiegard, Anika
AU - Benredjem, Hajar
AU - Jackson, Kathryn
AU - Liffers, Sven T.
AU - Lueong, Smiths
AU - Cheung, Phyllis F.
AU - Vangala, Deepak
AU - Pohl, Michael
AU - Viebahn, Richard
AU - Teschendorf, Christian
AU - Wolters, Heiner
AU - Usta, Selami
AU - Geng, Keyi
AU - Kutter, Claudia
AU - Arsenian-Henriksson, Marie
AU - Siveke, Jens T.
AU - Tannapfel, Andrea
AU - Schmiegel, Wolff
AU - Hahn, Stephan A.
AU - Baranello, Laura
N1 - Publisher Copyright:
© 2023 The Authors, some rights reserved;
PY - 2023/10
Y1 - 2023/10
N2 - Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor’s vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.
AB - Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor’s vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.
UR - http://www.scopus.com/inward/record.url?scp=85175586260&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adg5109
DO - 10.1126/sciadv.adg5109
M3 - Article
C2 - 37831776
AN - SCOPUS:85175586260
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 41
M1 - eadg5109
ER -
