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Sanij, Elaine; Hannan, Katherine M; Xuan, Jiachen; Yan, Shunfei; Ahern, Jessica E; Trigos, Anna S; Brajanovski, Natalie; Son, Jinbae; Chan, Keefe T; Kondrashova, Olga; Lieschke, Elizabeth; Wakefield, Matthew J; Frank, Daniel; Ellis, Sarah; Cullinane, Carleen; Kang, Jian; Poortinga, Gretchen; Nag, Purba; Deans, Andrew J; Khanna, Kum Kum; Mileshkin, Linda; McArthur, Grant A; Soong, John; Berns, Els M J J; Hannan, Ross D; Scott, Clare L; Sheppard, Karen E; Pearson, Richard B
Nature communications, 05/2020, Letnik: 11, Številka: 1Journal Article
Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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