The novel proautophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous nonsmall cell lung cancer
Anna López-Plana
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Search for more papers by this authorPatricia Fernández-Nogueira
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorPau Muñoz-Guardiola
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorSònia Solé-Sánchez
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorElisabet Megías-Roda
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorHéctor Pérez-Montoyo
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorPatricia Jauregui
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorMarc Yeste-Velasco
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorMariana Gómez-Ferreria
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorTatiana Erazo
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorElisabet Ametller
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorLeire Recalde-Percaz
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Search for more papers by this authorNúria Moragas-Garcia
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorAleix Noguera-Castells
Department of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorMario Mancino
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Department of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorTeresa Morán
Medical Oncology Department, Catalan Institute of Oncology - Badalona, Hospital Universitari Germans Trias i Pujol, Institut Germans Trias i Pujol, Badalona-Applied Research Group in Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorErnest Nadal
Department of Medical Oncology, Thoracic Oncology Multidisciplinary Unit, Catalan Institute of Oncology, Barcelona, Spain
Search for more papers by this authorJosé Alfón
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorCarles Domènech
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorPere Gascon
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Department of Medicine, University of Barcelona, Barcelona, Spain
Department of Medical Oncology, Hospital Clínic, Barcelona, Spain
Search for more papers by this authorJose M. Lizcano
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorCorresponding Author
Gemma Fuster
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Department of Biochemistry & Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
Department of Biosciences, Faculty of Sciences and Technology, University of Vic, Vic, Spain
Correspondence to: Gemma Fuster, E-mail: [email protected]; or Paloma Bragado, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Paloma Bragado
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
Correspondence to: Gemma Fuster, E-mail: [email protected]; or Paloma Bragado, E-mail: [email protected]Search for more papers by this authorAnna López-Plana
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Search for more papers by this authorPatricia Fernández-Nogueira
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorPau Muñoz-Guardiola
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorSònia Solé-Sánchez
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorElisabet Megías-Roda
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorHéctor Pérez-Montoyo
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorPatricia Jauregui
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorMarc Yeste-Velasco
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorMariana Gómez-Ferreria
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorTatiana Erazo
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorElisabet Ametller
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorLeire Recalde-Percaz
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Search for more papers by this authorNúria Moragas-Garcia
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Search for more papers by this authorAleix Noguera-Castells
Department of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorMario Mancino
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Department of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorTeresa Morán
Medical Oncology Department, Catalan Institute of Oncology - Badalona, Hospital Universitari Germans Trias i Pujol, Institut Germans Trias i Pujol, Badalona-Applied Research Group in Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorErnest Nadal
Department of Medical Oncology, Thoracic Oncology Multidisciplinary Unit, Catalan Institute of Oncology, Barcelona, Spain
Search for more papers by this authorJosé Alfón
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorCarles Domènech
Ability Pharmaceuticals, SL, Cerdanyola Del Vallès, Barcelona, Spain
Search for more papers by this authorPere Gascon
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Department of Medicine, University of Barcelona, Barcelona, Spain
Department of Medical Oncology, Hospital Clínic, Barcelona, Spain
Search for more papers by this authorJose M. Lizcano
Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
Search for more papers by this authorCorresponding Author
Gemma Fuster
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Biochemistry and Molecular Biomedicine Department, School of Biology, University of Barcelona, Barcelona, Spain
Department of Biochemistry & Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
Department of Biosciences, Faculty of Sciences and Technology, University of Vic, Vic, Spain
Correspondence to: Gemma Fuster, E-mail: [email protected]; or Paloma Bragado, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Paloma Bragado
Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
Correspondence to: Gemma Fuster, E-mail: [email protected]; or Paloma Bragado, E-mail: [email protected]Search for more papers by this authorAbstract
Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of survival and reduction of disease-related adverse events is the main goal for oncologists. In this scenario, we present preclinical evidence supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Nonsmall cell lung adenocarcinomas (NSCLC) and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first-in-human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induces AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy markedly increases the therapeutic effect of chemotherapy without increasing toxicity. We further show that combination of ABTL0812 and chemotherapy induces nonapoptotic cell death mediated by TRIB3 activation and autophagy induction. We also present preliminary clinical data indicating that TRIB3 could serve as a potential novel pharmacodynamic biomarker to monitor ABTL0812 activity administered alone or in combination with chemotherapy in squamous NSCLC patients. The safety profile of ABTL0812 and its good synergy with chemotherapy potentiate the therapeutic potential of current lines of treatment based on chemotherapy regimens, arising as a promising option for improving these patients therapeutic expectancy.
Abstract
What's new?
Non-small cell lung carcinoma is a common lung cancer with poor prognosis due to late diagnosis and frequent drug resistance of the tumor. Here the authors examined the cytotoxic effect of ABTL0812, a new AKT/mTOR inhibitor currently under clinical development, in combination with common chemotherapy regimens in lung squamous carcinoma cell lines. They demonstrate non-apoptotic cell death mediated by activation of the Tribbles-3 pseudokinase (TRIB3) and autophagy induction in response to ABTL0812 co-treatment, proposingTRIB3 as a potential new biomarker to monitor the activity of ABTL0812 treatment in human clinical trials.
Conflict of interest
ABTL0812 is a drug under development by Ability Pharmaceuticals. P.M-G., S.S-S., E.M-R., H.P-M., M.Y-V., C.D. and J.A. are Ability Pharmaceuticals employees; C.D. is a founder of Ability Pharmaceuticals and holds shares of the company; E.N. has received consultancy fees from Ability Pharmaceuticals; J.M.L. and P.G. are members of its Scientific Advisory Board.
Supporting Information
| Filename | Description |
|---|---|
| IJC_32865-sup-0001-Supinfo.pdfPDF document, 1.1 MB | Appendix S1: Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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