Evaluation of XL999, a Potent Inhibitor of FGFR3, for the Potential Treatment of t(4;14) Positive Multiple Myeloma.
Notice bibliographique
Résumé
Abstract Recent advances in our understanding of the molecular pathogenesis of Multiple Myeloma (MM) have provided novel therapeutic targets for treatment of this incurable malignancy. The association of Fibroblast Growth Factor Receptor 3 (FGFR3) with the t(4;14) translocation that occurs uniquely in approximately 15% of MM patients, coupled with the demonstration of the transforming potential of this receptor tyrosine kinase (RTK), make this a particularly attractive target for the development of therapeutic agents for this poor prognosis group. Indeed, inhibition of activated FGFR3 induces apoptosis and inhibits growth in mice of FGFR3-expressing MM tumors, providing further validation of this RTK as a therapeutic target in t(4;14) MM. XL999 is a novel small molecule inhibitor of kinases involved in tumor cell growth and angiogenesis, and is currently in a Phase 1 clinical trial in patients with non-small cell lung cancer. XL999 inhibits members of the class III-V RTKs, including FGFR1 and 3, VEGFR2, PDGFR? and ?, KIT, and FLT3, and exhibits pharmacodynamic target modulation, anti-angiogenesis, and efficacy in multiple tumor models in mice (Eur. J. Cancer Suppl. 2: 141). We report here the FGFR3-targeting characteristics and anti-myeloma activity of XL999. XL999 inhibits FGFR3 with low nanomolar potency in biochemical enzyme assays. Therefore, we examined the activity of XL999 in several cell-based mechanistic assays of FGFR3 activity. The IL-6 dependent cell line, B9, was engineered to express wild-type or activated mutants (Y373C, K650E, G384D and J807C) of FGFR3 found in MM. XL999 differentially inhibited FGF-mediated growth of B9 cells expressing wild-type and mutant receptors, with IC50 values in the low nM range. Growth of these cells could be rescued by IL-6, indicating selectivity of XL999 for FGFR3. The activity of XL999 against FGFR3 was also examined in t(4;14) positive MM cell lines expressing FGFR3. XL999 inhibited the proliferation and viability of KMS-11 cells (FGFR3-Y373C) and OPM-2 cells (expressing FGFR3-K650E) with low nM potency. Importantly, inhibition by XL999 was still observed in the presence of IL-6 or IGF1, potent growth factors for MM cells. In addition, XL999 potently inhibited the phosphorylation of FGFR3 in OPM-2 and KMS-11 tumors after a single oral dose in pharmacodynamic studies in nude mice. U266 and 8226 cells, which lack FGFR3 expression, displayed minimal growth inhibition by XL999, demonstrating that at effective concentrations, XL999 is selective and exhibits minimal nonspecific cytotoxicity to FGFR3 negative MM cells. Further characterization of this finding demonstrated that inhibition of cell growth corresponded to G0/G1 cell cycle arrest, dose-dependent inhibition of downstream ERK phosphorylation, and induction of apoptosis in FGFR3-positive cells. In vitro analysis of XL999 combined with melphalan, bortezomib, or dexamethasone applied simultaneously to KMS11 cells indicated a strong synergistic interaction with dexamethasone, and additivity with either melphalan or bortezomib. Finally, XL999 produced cytotoxic responses in 5/5 primary myeloma samples derived from patients harboring a t(4;14) translocation. Collectively, these results suggest that XL999 may hold potential for patients with MM, particularly in combination with other agents.
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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 | 0,001 | 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) | 0,000 | 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 ».