Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer

Autor: Anna Adam-Artigues, Enrique J. Arenas, Alex Martínez-Sabadell, Fara Brasó-Maristany, Raimundo Cervera, Eduardo Tormo, Cristina Hernando, María Teresa Martínez, Juan Carbonell-Asins, Soraya Simón, Jesús Poveda, Santiago Moragón, Sandra Zazo, Débora Martínez, Ana Rovira, Octavio Burgués, Federico Rojo, Joan Albanell, Begoña Bermejo, Ana Lluch, Aleix Prat, Joaquín Arribas, Pilar Eroles, Juan Miguel Cejalvo
Přispěvatelé: Institut Català de la Salut, [Adam-Artigues A, Cervera R] INCLIVA Biomedical Research Institute, Valencia, Spain. [Arenas EJ] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. [Martínez-Sabadell A] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Brasó-Maristany F] August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. [Tormo E] INCLIVA Biomedical Research Institute, Valencia, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. [Arribas J] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain. Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
Jazyk: angličtina
Rok vydání: 2023
Předmět:
fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS]
neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES]
Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance
Neoplasm [PHENOMENA AND PROCESSES]
Multidisciplinary
Receptor
ErbB-2
Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES]
Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores]
Breast Neoplasms
Trastuzumab
Other subheadings::Other subheadings::/drug therapy [Other subheadings]
Càncer de mama
Càncer--Tractament
Phosphatidylinositol 3-Kinases
Breast cancer
Drug Resistance
Neoplasm
Cell Line
Tumor
Drug resistance
Mama - Càncer - Tractament
Mama--Càncer
Humans
Female
Tumors
Resistència als medicaments
Zdroj: Science Advances
r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
Consejo Superior de Investigaciones Científicas (CSIC)
Scientia
ISSN: 2375-2548
Popis: Breast cancer; Heterodimerization Cáncer de mama; Heterodimerización Càncer de mama; Heterodimerització Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer. A.A.-A., E.J.A., and F.B.-M. were supported by Asociación Española contra el Cáncer AECC (PRDVA18013LLUC to A.A.-A., POSTD211413AREN to E.J.A., and AECC_Postdoctoral17-1062 to F.B.-M.). A.M.-S. was funded by the Spanish Government (PFIS FI20/00188). J.Ar. is supported by Breast Cancer Research Foundation (BCRF-20-08), Instituto de Salud Carlos III Project reference number AC15/00062, and the EC under the framework of the ERA-NET TRANSCAN-2 initiative cofinanced by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181), and Asociación Española Contra el Cáncer (AECC). A.P. was supported by Instituto de Salud Carlos III—PI19/01846, Breast Cancer Now—2018NOVPCC1294. P.E. and A.L. were funded by Instituto de Salud Carlos III and cofinanced by FEDER (PI18/01219 to P.E. and CB16/12/00481 to A.L.). J.M.C. was funded by Sociedad Española de Oncología Médica (Rio Hortega-SEOM) and Compromiso ADAMED.
Databáze: OpenAIRE
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