Abstract 2019: Synergistic anticancer activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein
Notice bibliographique
Résumé
Abstract Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the selective toxicity that some chemotherapy drugs have for cancer cells. This "synthetic lethality" (Nature 434:913, ‘05) can be enhanced by agents that inhibit DNA repair (Mol Onc 8:1429, ‘14; Proc AACR 57:3718, ‘16). To exploit this potential "Achilles heel", we tested the ability of a small molecule inhibitor of RAD51 to potentiate the cytotoxicity of established chemotherapy drugs. 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) was obtained from Drs. J-W Zhu and W-H Lee (Univ. California - Irvine). IBR2 inhibits RAD51-mediated double-strand DNA break repair, but also enhances induction of apoptosis by the ABL inhibitor imatinib against K562 cells (EMBO Mol Med 5:353, ‘13). There is potential value of such synergistic interaction among other tumor types and with other drugs. IBR2-drug combinations were therefore examined across a spectrum of cancer cell lines from various tissues (AML, CML, carcinoma of breast, colon, stomach, lung, and head) representing a range of oncogenic drivers (ABL, c-kit, Raf, Ras, ER, mutant p53). Cells were exposed to IBR2 simultaneously with inhibitors of various tyrosine kinase receptors, DNA-damaging agents, or inhibitors of microtubule function. Cells were cultured in 96-well plates, exposed to drugs alone and in combination, and cell density determined by viability staining (alamarBlue or neutral red) 4 days later. Inhibition of proliferation by drug combinations was normalized to that of IBR2 alone. Depending on the drug sensitivity of the cell line, IBR2, at concentrations that inhibited proliferation between 0% and 75% as a single agent, enhanced toxicity of imatinib by up to 80%. IBR2 also greatly enhanced antiproliferative activity of regorafenib (targets RAF, kit, others), EGFR inhibitors erlotinib, gefitinib, afatinib and osimertinib, and microtubule inhibitor vincristine (VCR). However, IBR2 was antagonistic with VP-16, cisplatin, irinotecan, melphalan, and olaparib. To determine a possible mechanism of the observed synergy, the interaction between IBR2 and imatinib or VCR was compared with that between verapamil, a P-glycoprotein inhibitor, and the latter 2 drugs. The VCR-resistant head and neck cell line HN-5a/V15e was not cross-resistant to imatinib, but IBR2 enhanced imatinib toxicity in this cell line, its HN-5a parent, and HT-29 by up to 60%, much better than verapamil (up to 40% at similar concentrations, P<0.05). IBR2 enhanced VCR toxicity in these 3 lines to degree similar to verapamil, decreasing the IC50 by up to 90%. IBR2 appears to enhance drug toxicities via mechanisms other than just inhibition of RAD51 and may potentially interfere with microtubule function. The results indicate that this agent may be useful as a clinical adjuvant to numerous cytotoxic drugs. Citation Format: Peter J. Ferguson, Mark D. Vincent, James Koropatnick. Synergistic anticancer activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2019. doi:10.1158/1538-7445.AM2017-2019
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».