Abstract 350: AUTX-703, a novel and potent KAT2A and KAT2B protein degrader, induces differentiation and provides a potential therapeutic opportunity in subtypes of prostate cancer
Notice bibliographique
Résumé
Abstract Introduction: Phenotypic plasticity, or the ability of cancer cells to switch between cell states, is a hallmark of cancer. Cancer cells can hijack normal developmental pathways and push cells to a more proliferative, plastic cell state similar to those found in early development. To identify therapeutic targets driving tumor plasticity, we utilized our proprietary AI-ML platform to create a high resolution atlas of normal human development. Tumors were mapped to the atlas to identify the genes driving their oncogenic cell state. Our platform identified KAT2A, a lysine acetyltransferase, as a key driver in neuroendocrine prostate cancer (NEPC). Additionally in castration resistant prostate cancer (CRPC), elevated expression of KAT2A has been reported in patients with high grade disease or biochemical recurrence and is associated with poor clinical survival. Literature has demonstrated that shKAT2A can modify resistance to anti-androgens and suggests that KAT2A can play a role in the localization of androgen receptor (AR). Our studies investigate the opportunity for targeting KAT2A in treatment refractory prostate cancer (NEPC and CRPC). Methods: To pharmacologically target KAT2A, and its paralog KAT2B, we developed AUTX-703, a novel, potent and orally bioavailable heterobifunctional protein degrader. The effects of AUTX-703 on cellular differentiation and growth inhibition were evaluated in NEPC cell lines and patient derived organoids models. The effects of AUTX-703 on AR localization and signaling were also evaluated in cell lines resistant to anti-androgens. Results: Treatment of the NEPC cell line, LASCPC01 and two NEPC organoid models with AUTX-703 degraded KAT2A and KAT2B, induced differentiation toward an epithelial cell state and inhibited growth, in vitro. In AR positive treatment refractory prostate adenocarcinoma models, AUTX-703 alone or in combination with anti-androgens reduced cell growth, decreased levels of nuclear AR, and decreased levels of AR and Myc signaling. Unlike anti-androgen treatment which shifted cells toward a more stem-like state, treatment with AUTX-703 alone or in combination with anti-androgens shifted cells towards a more differentiated epithelial cell state. Conclusion: Our studies validate KAT2A and KAT2B as key drivers of tumor cell state plasticity. Degradation of KAT2A and KAT2B with AUTX-703 induces a more differentiated cell state and inhibits growth in NEPC and CRPC models. These data support progression of AUTX-703 into clinical development for NEPC and targeting KAT2A and KAT2B in the treatment of anti-androgen resistant prostate cancer. Citation Format: Sara L. Sinicropi-Yao, Joe DeBartolo, Umar Sharif, Zied Boudhraa, Mohamed El Ezzy, Sambad Sharma, Maulasri Bhatta, Christina Lee, Betty Chan, Henry Wilson, James Neef, Mark Bittenger, Laura Antipov, Thomas G. Graeber, David S. Millan, Katharine E. Yen, Kimberly S. Straley. AUTX-703, a novel and potent KAT2A and KAT2B protein degrader, induces differentiation and provides a potential therapeutic opportunity in subtypes of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 350.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».