Abstract LB-114: GC1118, a new anti-EGFR antibody overcome acquired resistance to cetuximab in colorectal cancer xenograft model
Notice bibliographique
Résumé
Abstract Purpose: Anti-epidermal growth factor receptor (EGFR) antibodies such as cetuximab and panitumumab are widely used to treat patients with metastatic colorectal cancer (mCRC). However, patients eventually develop resistance to these drugs, which is one of the biggest challenges of EGFR-targeted therapy. Retrospective clinical studies revealed that mCRC patients with higher expression of low-affinity EGFR ligands such as amphiregulin and epiregulin had longer median progression free survival. On the contrary, patients refractory to cetuximab tended to have higher level of TGF-α expression according to the gene expression analysis. Recently, we demonstrated that GC1118 is a prominent blocker of both high- and low-affinity EGFR ligands induced signaling while cetuximab is limited to low-affinity ligands. In this study, we generated and characterized cetuximab-resistant CRC cell line and tested anti-tumor efficacy of GC1118 on cetuximab-resistant CRC tumor models. Experimental Design: To develop cetuximab-resistant SW48 colon cancer cell line (SW48CR) in vivo, mice bearing SW48 xenograft colorectal tumors were continuously exposed to cetuximab for several months. K-Ras mutation was analyzed by PCR and EGFR ligand expression was determined by ELISA assay. Results: First, we determined K-Ras mutation status and EGFR expression to characterize SW48CR cell line. K-Ras mutation is one of the most well-known cetuximab resistance mechanisms in CRC. There was no difference in EGFR expression level between SW48 and SW48CR. K-Ras expression was slightly increased and constitutively activated in SW48CR without mutation. Cetuximab resistance was confirmed by measuring proliferation and EGFR signaling inhibition by cetuximab in vitro. As expected, cetuximab was incapable of inhibiting cell proliferation and EGFR downstream signals in SW48CR cell line. Using SW48CR xenograft mouse model, we found that GC1118 suppressed SW48CR tumor growth by 80% while cetuximab inhibited less than 35%. Despite of this potent anti-tumor efficacy of GC1118 in vivo, GC1118 had no effect on SW48CR proliferation in vitro. This indicated GC1118 anti-tumor effect on SW48CR may be related to tumor microenvironment. In addition, EGFR ligand expression analysis indicated that HB-EGF, one of the high-affinity EGFR ligands was significantly increased in SW48CR compared with SW48, as previously reported by others. Since high-affinity EGFR ligands such as HB-EGF and TGF-α were implicated in tumor microenvironment, we are currently investigating GC1118 effects on tumor vasculature of SW48CR xenograft by immunohistochemical staining. Conclusion: These results suggest that overexpression of HB-EGF may contribute to cetuximab resistant CRC and GC1118 could be rational strategy to treat patients who acquired cetuximab resistance. Citation Format: Shi-Nai Lee, Hyun-Jung Cho, Yangmi Lim, Minkyu Hur, Eun Hee Lee, Jae-Chul Lee, Kyuhyun Lee, Sujeong Kim, Jonghwa Won. GC1118, a new anti-EGFR antibody overcome acquired resistance to cetuximab in colorectal cancer xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-114.
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) | 0,000 | 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 | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».