2016
DOI: 10.1016/j.ygyno.2016.07.088
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Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Abstract: Objective Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib. Methods Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 … Show more

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Cited by 33 publications
(43 citation statements)
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“…Our group and others have shown that in BRCA wildtype HR proficient tumors, epigenetic drugs including BETi, induce a HR deficient phenotype and sensitize tumors to PARPi [22,23,28,29]. PARPi and epigenetic drug combinations result in reduced HR proficiency, downregulation of cyclin E expression and increased DNA damage and apoptosis [22,29]. Thus, novel PARPi and epigenetic drug combinations may prove to be an effective strategy in platinum-resistant CCNE1 and BRD4 amplified tumors, a subset of poor prognostic HR proficient HGSOC.…”
Section: Discussionmentioning
confidence: 93%
See 1 more Smart Citation
“…Our group and others have shown that in BRCA wildtype HR proficient tumors, epigenetic drugs including BETi, induce a HR deficient phenotype and sensitize tumors to PARPi [22,23,28,29]. PARPi and epigenetic drug combinations result in reduced HR proficiency, downregulation of cyclin E expression and increased DNA damage and apoptosis [22,29]. Thus, novel PARPi and epigenetic drug combinations may prove to be an effective strategy in platinum-resistant CCNE1 and BRD4 amplified tumors, a subset of poor prognostic HR proficient HGSOC.…”
Section: Discussionmentioning
confidence: 93%
“…CCNE1 and/or BRD4 amplified HR proficient HGSOC (~30%) represent a substantial population for developing novel drug combinations. Our group and others have shown that in BRCA wildtype HR proficient tumors, epigenetic drugs including BETi, induce a HR deficient phenotype and sensitize tumors to PARPi [22,23,28,29]. PARPi and epigenetic drug combinations result in reduced HR proficiency, downregulation of cyclin E expression and increased DNA damage and apoptosis [22,29].…”
Section: Discussionmentioning
confidence: 96%
“…Finally, HR proficient OC with concurrent amplification of cyclin-E genes has been demonstrated to be resistant to PARPis [62]. As a consequence, the rationale to combine PARPis with molecularly targeted agents capable of inhibiting HRR may represent a promising effective strategy to expand their use in HR-proficient OC [63]. Among all the combinations that are currently under assessment, the association with PI3K inhibitors appears the most reasonable approach, as its phase I evaluation in ovarian and triple-negative breast cancers has just been completed [64].…”
Section: Parpis and Other Agentsmentioning
confidence: 99%
“…Ibrahim and collaborators [71] demonstrated that phosphoinositide 3-kinase (PI3K) inhibition could be exploited to induce HR deficiency and sensitization to PARPis in BRCA-proficient triple-negative breast cancers, since PI3K closely interacts with the HR complex in order to stabilize and preserve DSB repair, while other researchers focused their attention on exploring the role played by epigenetic mechanisms in HR efficiency. In particular, Vorinostat [72] and Panobinostat [73], two histone deacetylase inhibitors (HDACis), were shown to downregulate genes implicated in HR DNA repair, such as cyclin E, E2F1, and BRCA1, in HR-proficient ovarian cancer cells, leading to synergistic enhancement of cytotoxicity when these compounds were combined with the PARPi Olaparib. Of note, the cytotoxic effect of the combination between Panobinostat and Olaparib was striking chiefly in cyclin E-overexpressing HR-proficient ovarian tumor cells.…”
Section: Issues With the Management Of Hr Proficiency In Hgsocmentioning
confidence: 99%
“…Of note, the cytotoxic effect of the combination between Panobinostat and Olaparib was striking chiefly in cyclin E-overexpressing HR-proficient ovarian tumor cells. This finding could be explained by the intrinsic reliance of cyclin E-overexpressing HGSOCs on high levels of HR proficiency; indeed, since amplified cyclin E is a well-known oncogenic driver of unchecked replication which leads to replicative stress and great genomic instability, cyclin E-overexpressing ovarian tumors are strictly dependent on robust HR DNA repair mechanisms for their survival [73].…”
Section: Issues With the Management Of Hr Proficiency In Hgsocmentioning
confidence: 99%