Combined MEK and PI3K/p110b inhibition as a novel targeted therapy for malignant mesothelioma displaying sarcomatoid features

Autor: Christine Pirker, Natalia del Pozo, Francisco X. Real, Jaime Martinez de Villarreal, Clément Meiller, Amancio Carnero, Luis C. Fernández, Walter Berger, Yuna Blum, Miriam Marqués, Didier Jean, Enrique Carrillo-de-Santa-Pau, Balazs Hegedus, Yves Allory, Blanca Risa-Ebrí, María L. Suárez-Solís, Simon T. Barry, Robin Tranchant
Přispěvatelé: Epithelial Carcinogenesis Group [Madrid, Spain], Spanish National Cancer Research Center (CNIO), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Universidad Europea de Madrid, IMDEA Food Institute [Madrid, Spain], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Comprehensive Cancer Center [Vienna, Austria], Institute of Cancer Research [Vienna, Austria]-Medizinische Universität Wien = Medical University of Vienna, Medizinische Universität Wien = Medical University of Vienna, IMED Oncology [Cambridge, UK] (AstraZeneca), Li Ka Shing Centre [Cambridge, UK], Instituto de Biomedicina de Sevilla [Sevilla, Spain] (IBIS/HUVR), Universidad de Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Departament de Ciències Experimentals i de la Salut [Barcelona, Spain], Universitat Pompeu Fabra [Barcelona] (UPF), This work was supported, in part, by grants from Asociación Española Contra el Cáncer (FXR), Spanish Ministry of Economy and Competitivity, Plan Estatal de I+D+I 2013-2016, ISCIII (FIS PI15/00045) (AC), RTICC (Instituto de Salud Carlos III, grants RD12/0036/0034 to FXR and AC, respectively), and CIBERONC (CB16/12/00453 and CD16/12/00275 to FXR and AC, respectively), cofunded by FEDER from Regional Development European Funds (European Union) and Inserm (Institut national de la santé et de la recherche médicale). MM was supported by a Sara Borrell Fellowship from Instituto de Salud Carlos III. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510., Jean, Didier, Universidad Europea de Madrid = European University of Madrid (UEM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Medizinische Universität Wien = Medical University of Vienna-Institute of Cancer Research [Vienna, Austria], Universidad de Sevilla / University of Sevilla-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Mesothelioma
0301 basic medicine
MAPK/ERK pathway
Cancer Research
Lung Neoplasms
medicine.medical_treatment
Vimentin
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
PI3K
Epithelium
Targeted therapy
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Gene Knock-In Techniques
Molecular Targeted Therapy
Peritoneal Neoplasms
Mice
Knockout
Aniline Compounds
biology
Cáncer
Prognosis
3. Good health
Oncology
Terapia
030220 oncology & carcinogenesis
Pleura
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
Female
Peritoneum
Class I Phosphatidylinositol 3-Kinases
Pleural Neoplasms
Primary Cell Culture
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
GPCRs
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
medicine
Animals
Humans
PTEN
Protein Kinase Inhibitors
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
PI3K/AKT/mTOR pathway
Cell Proliferation
Mitogen-Activated Protein Kinase Kinases
business.industry
Mesothelioma
Malignant
PTEN Phosphohydrolase
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
medicine.disease
Sarcomatoid Mesothelioma
MAPK
Disease Models
Animal
Mesotelioma
030104 developmental biology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Chromones
biology.protein
Selumetinib
Cancer research
Benzimidazoles
Tumor Suppressor Protein p53
sarcomatoid mesothelioma
business
Zdroj: Cancer Research
Cancer Research, American Association for Cancer Research, 2020, 80 (4), pp.843-856. ⟨10.1158/0008-5472.CAN-19-1633⟩
Cancer Research, 2020, 80 (4), pp.843-856. ⟨10.1158/0008-5472.CAN-19-1633⟩
Digital.CSIC. Repositorio Institucional del CSIC
instname
ABACUS. Repositorio de Producción Científica
Universidad Europea (UEM)
ISSN: 0008-5472
1538-7445
DOI: 10.1158/0008-5472.CAN-19-1633⟩
Popis: Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.
[Significance] Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.
This work was supported, in part, by grants from Asociación Española Contra el Cáncer (F.X. Real), Spanish Ministry of Economy and Competitivity, Plan Estatal de I+D+I 2013-2016, ISCIII (FIS PI15/00045 to A. Carnero), RTICC (Instituto de Salud Carlos III, grants RD12/0036/0034 to F.X. Real and A. Carnero, respectively), and CIBERONC (CB16/12/00453 and CD16/12/00275 to F.X. Real and A. Carnero, respectively), cofunded by FEDER from Regional Development European Funds (European Union) and Inserm (Institut national de la santé et de la recherche médicale). M. Marqués was supported by a Sara Borrell Fellowship from Instituto de Salud Carlos III. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510.
Databáze: OpenAIRE
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