Pignataro, Claudia (2025) Microenvironment-mediated crizotinib resistance in ALK⁺ Anaplastic Large Cell Lymphoma: overcoming stromal protection through BH3 mimetic drugs. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Microenvironment-mediated crizotinib resistance in ALK⁺ Anaplastic Large Cell Lymphoma: overcoming stromal protection through BH3 mimetic drugs |
| Autori: | Autore Email Pignataro, Claudia claudia.pignataro@unina.it |
| Data: | 8 Dicembre 2025 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 38 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Fiore, Danilo [non definito] |
| Data: | 8 Dicembre 2025 |
| Parole chiave: | Lymphoma, Microenvironment, BH3 mimetics, Anaplastic Large cell Lymphoma, Crizotinib. |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/05 - Patologia clinica Area 06 - Scienze mediche > MED/06 - Oncologia medica Area 06 - Scienze mediche > MED/15 - Malattie del sangue |
| Informazioni aggiuntive: | 38° ciclo di dottorato in Medicina Molecolare e Biotecnologie Mediche |
| Depositato il: | 22 Dic 2025 10:02 |
| Ultima modifica: | 12 Ago 2026 05:39 |
| URI: | https://www.fedoa.unina.it/id/eprint/17062 |
Abstract
Anaplastic Large Cell Lymphoma (ALCL) is an aggressive subtype of peripheral T-cell lymphoma characterized by resistance to both conventional chemotherapy and targeted agents (crizotinib). In ALK⁺ ALCL the ALK inhibitor, crizotinib induces rapid and strong responses, particularly in pediatric and young adult patients. However, most patients relapse within a short timeframe, suggesting that early persistence mechanisms significantly contribute to relapsed/refractory phenotypes. The aim of this thesis was to dissect the molecular basis of crizotinib resistance, with a focus on the role of the tumor microenvironment and to assess whether inhibiting anti-apoptotic proteins could counteract the protective effect exerted by stromal cells on ALK⁺ ALCL cells exposed to ALK inhibition. By integrating bulk and single-cell transcriptomic analyses with functional drug assays, we showed that stromal cells deliver pro-survival signals that attenuate crizotinib-induced apoptosis and promote the emergence of persister populations. ALK⁺ ALCL cells challenged with crizotinib increased BCL2 expression and displayed transcriptional changes consistent with reduced apoptotic priming. The single-cell analysis revealed a cluster of ALK⁺ ALCL cells overrepresented after crizotinib treatment, characterized by MYC activation, metabolic rewiring, and apoptotic escape, providing novel insights into the heterogeneity of drug persistence. Finally, we demonstrated that the pharmacological and genetic inhibition of BCL2 family members synergized with crizotinib and effectively neutralized the protective influence of stromal cells in ALK⁺ ALCL systems, both in vitro and in vivo. Collectively, these findings highlight the dual contribution of intrinsic adaptations and extrinsic stromal cues in sustaining crizotinib persistence and support the clinical evaluation of BH3 mimetics as rational combinatorial partners of ALK inhibitors to improve therapeutic outcomes in ALK⁺ ALCL.
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