Abstract IA25: Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway
Notice bibliographique
Résumé
Abstract Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. HRR alterations have also been identified, albeit less frequently, in other human malignancies including triple negative breast, prostate, and pancreatic cancers. The most commonly altered HRR genes are BRCA1 and BRCA2 followed by other Fanconi Anemia (FA) genes (e.g. PALB2, FANCA, FANCI, FANCL, and FANCC), core RAD genes (e.g. RAD50, RAD51, RAD51C, and RAD54L) and DNA damage response genes involved in HRR, such as ATM, ATR, CHEK1, and CHEK2. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to certain types of DNA-damaging chemotherapy such as platinum analogues and topoisomerase inhibitors. HRR deficient tumors are also exquisitely sensitive to PARP-inhibitors (PARPis) which exhibit synthetic lethality to cells with defective HRR. This synthetic lethal interaction is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations who have progressed through at least 3 prior lines of therapy. The efficacy of PARPis against HRR deficient cells can be explained by various mechanisms including inhibition of base excision repair (BER), trapping of PARP-DNA complexes at the replication fork, enhancement of toxic non-homologous end joining in PARP1-deficient cells, and inhibition of PARP1/Polθ-mediated alternative end joining (alt-EJ). Underlying HRR deficiency is important for the cytotoxicity of PARPis and this is highlighted by the fact that the most prevalent mechanism of PARPi resistance is secondary genetic and epigenetic events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HR proficiency via reduced uptake and increased efflux of the drugs or via disruption of multiple proteins such as PTIP or CHD4 that leads to replication fork protection. Importantly, this latter mechanism-namely, the restoration of RF stability- appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. In my presentation, I will discuss new mechanisms of RF nucleolytic degradation and novel mechanisms by which tumors can avoid this degradation and acquire PARP inhibitor resistance. A molecular understanding PARP inhibitor resistance mechanisms is important, since it may allow the generation of a new class of drugs, or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types. Citation Format: Alan D. D'Andrea. Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA25.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».