Abstract 6908: Autophagy disruption via PIKfyve inhibition as a novel strategy to enhance immunotherapy responses in multiple myeloma
Notice bibliographique
Résumé
Abstract Despite advancements in the treatment of multiple myeloma (MM), most patients ultimately relapse due to innate and acquired drug resistance. Our search for novel therapeutic strategies led to the development of PIK001, a potent and selective PIKfyve inhibitor, as a promising therapeutic approach targeting lysosomal function and autophagy. In addition to its robust single agent anti-MM activity, PIK001 presented synergistic activity with relevant anti-MM therapeutics, including selinexor, venetoclax, and pomalidomide (IMiDs), in vitro. Notably, PIK001 retained efficacy in IMiD-resistant isogenic human myeloma cell line (HMCL) models, underscoring its potential in drug-resistant MM. To investigate the determinants of PIKfyve resistance, we generated PIK001-resistant HMCLs by culturing three PIK001-sensitive HMCLs (KMS26, KMS11, and JJN3) in escalating doses of the PIKfyve inhibitor (up to 5uM). These isogenic models of resistance were characterized by whole genome and transcriptome sequencing and mass spectrometry-based proteomics. Ex vivo downstream effects of PIK001 treatment with 500nM for 16h were further assessed in patient-derived CD138+ MM samples using single-cell multiomic sequencing. PIK001 resistance was associated with a marked upregulation of genes and proteins involved in lysosomal function, autophagy regulation, and cholesterol homeostasis, along with downregulation of MYC targets. These findings were also found in primary patient samples following PIK001 treatment. KMS26 PIK001-resistant showed a clonal PIKFYVE kinase domain mutation, previously described in a resistant diffuse large B-cell lymphoma cell line. Importantly, we observed a two-fold increase in canonical and noncanonical Major Histocompatibility Complex (MHC) class I and a four-fold increase in MHC class II gene and protein expression in the PIK001-resistant compared to PIK001-sensitive KMS11. Increased cell surface expression of MHC Class I and II in KMS11 PIK001-resistant was confirmed by flow cytometry. PIK001-resistant KMS26 and JJN3 also presented an upregulation of cell surface expression of MHC Class I and, to a lesser extent, II. Similarly, PIK001 treatment also resulted in increased in MHC Class I gene expression on primary patient samples. Since downregulation or loss of MHC Class I has been shown as a mechanism of immune evasion in cancer, these findings suggest that PIKfyve inhibition may enhance MM immunotherapy responses by upregulating MHC surface expression. This hypothesis aligns with recent studies demonstrating increased tumor-specific MHC Class I expression and improved cancer immunotherapy efficacy following PIKfyve inhibition in solid tumors. Together, these results highlight the potential of PIKfyve inhibitors to synergize with existing anti-MM therapeutics and sensitize MM cells to MHC-dependent immunotherapies via autophagy disruption. Citation Format: Cecilia Bonolo de Campos, Dor D. Abelman, Ruijuan He, Tessa Pelino, Ding Yan Wang, David S. Scott, Zhihua Li, Michael St Paul, Trevor J. Pugh, Olga Issakova, Nikolai Sepetov, Tak W. Mak, Suzanne Trudel, A Keith Stewart. Autophagy disruption via PIKfyve inhibition as a novel strategy to enhance immunotherapy responses in multiple myeloma [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 6908.
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) | 0,001 | 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 ».