Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Parejo-Alonso, Beatriz ; Royo-García, Alba ; Espiau-Romera, Pilar ; Courtois, Sarah ; Curiel-García, Álvaro ; Zagorac, Sladjana ; Villaoslada, Isabel ; Olive, Kenneth P. ; Heeschen, Christopher ; Sancho, Patricia

Resumen: Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients.

Idioma: Inglés

DOI: 10.1016/j.biopha.2022.114162

Año: 2023

Publicado en: BIOMEDICINE & PHARMACOTHERAPY 158 (2023), 114162 [14 pp.]
ISSN: 0753-3322

Factor impacto JCR: 6.9 (2023)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 15 / 354 = 0.042 (2023) - Q1 - T1
Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 22 / 189 = 0.116 (2023) - Q1 - T1

Factor impacto CITESCORE: 11.9 - Pharmacology (Q1)

Factor impacto SCIMAGO: 1.493 - Pharmacology (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP29-21
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI17-00082
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI20-00921
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FI21-00031
Financiación: info:eu-repo/grantAgreement/ES/MS-ISCIII-FSE/CP16-00121

Tipo y forma: Article (Published version)