MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia
Manzano-Muñoz, A. (Institut de Bioenginyeria de Catalunya)
Alcon, Clara (Institut de Bioenginyeria de Catalunya)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ramírez, Manuel (Department of Pediatric Hematology and Oncology. Niño Jesús University Children's Hospital)
Seyfried, F. (Department of Pediatrics and Adolescent Medicine. Ulm University Medical Center)
Debatin, K.M. (Department of Pediatrics and Adolescent Medicine. Ulm University Medical Center)
Meyer, L.H. (Department of Pediatrics and Adolescent Medicine. Ulm University Medical Center)
Samitier, J. (Networking Biomedical Research Center in Bioengineering. Biomaterials and Nanomedicine (CIBER-BBN))
Montero, J. (Institut de Bioenginyeria de Catalunya)

Fecha:	2021
Resumen:	Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 - a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.
Ayudas:	Ministerio de Economía y Competitividad RYC-2015-18357 Ministerio de Economía y Competitividad RD16/0006/0012 Agencia Estatal de Investigación RTI2018-094533-A-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1079
Nota:	JM acknowledges the Ramon y Cajal Program, Ministerio de Economia y Competitividad (RYC-2015-18357) and the Spanish National Plan "Retos Investigacion" I + D + i (RTI2018-094533-A-I00) from Ministerio de Ciencia, Innovación y Universidades. This work was supported by the CELLEX foundation and the Networking Biomedical Research Center (CIBER), Spain. CIBER is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and the Instituto de Salud Carlos III (RD16/0006/0012), with the support of the European Regional Development Fund (ERDF). This work was also partially funded by the CERCA Program and by the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (2017 SGR 1079). FS: Medical Faculty of Ulm University (Clinician Scientist Programme). K-MD and LM: German Research Foundation (DFG, SFB 1074).
Nota:	We would like to thank to the Cytometry Facility from the University of Barcelona for assistance with flow cytometry experiments and Virginia Rodriguez for helping with the cell lines used in this manuscript.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Pediatric leukemia ; Targeted therapies ; Resistance ; Apoptosis ; BH3 mimetics
Publicado en:	Frontiers in Cell and Developmental Biology, Vol. 9 (september 2021) , art. 695225, ISSN 2296-634X

DOI: 10.3389/fcell.2021.695225
PMID: 34568318

15 p, 2.1 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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