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BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or B...

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Autores principales: Champion, Ophélie, Soler, Alana, Maïga, Sophie, Bellanger, Céline, Pellat-Deceunynck, Catherine, Talbot, Alexis, Touzeau, Cyrille, Amiot, Martine, Gomez-Bougie, Patricia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393035/
https://www.ncbi.nlm.nih.gov/pubmed/37534243
http://dx.doi.org/10.3389/fonc.2023.1196005
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author Champion, Ophélie
Soler, Alana
Maïga, Sophie
Bellanger, Céline
Pellat-Deceunynck, Catherine
Talbot, Alexis
Touzeau, Cyrille
Amiot, Martine
Gomez-Bougie, Patricia
author_facet Champion, Ophélie
Soler, Alana
Maïga, Sophie
Bellanger, Céline
Pellat-Deceunynck, Catherine
Talbot, Alexis
Touzeau, Cyrille
Amiot, Martine
Gomez-Bougie, Patricia
author_sort Champion, Ophélie
collection PubMed
description Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. Accordingly, BH3 profiling of 2 sPCL sensitive to BCLXL inhibition confirmed their high BCLXL primed profile. While targeting BCLXL using BH3 mimetics induces platelets on-target drug toxicity, the recent development of DT2216, a clinical-stage BCLXL proteolysis targeting chimera PROTAC compound, provides an alternative strategy to target BCLXL. Indeed, DT2216 specifically degrades BCLXL via VHL E3 ligase, without inducing thrombocytopenia. We demonstrated in human myeloma cell lines and sPCL that sensitivity to DT2216 strongly correlated with the sensitivity to A1155463. Interestingly, we showed that low doses of DT2216 (nM range) were sufficient to specifically degrade BCLXL after 48 hours of treatment, consistent with VHL expression, in all cell lines but irrespectively to DT2216 sensitivity. In myeloma cells, DT2216 induced apoptotic cell death and triggered BAX and BAK activation. In conclusion, our study demonstrated that patients with sPCL addicted to BCLXL, a small but a very challenging group, could potentially receive therapeutic benefit from DT2216. Clinical trials of DT2216 in this subset of sPCL patients are warranted.
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spelling pubmed-103930352023-08-02 BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival Champion, Ophélie Soler, Alana Maïga, Sophie Bellanger, Céline Pellat-Deceunynck, Catherine Talbot, Alexis Touzeau, Cyrille Amiot, Martine Gomez-Bougie, Patricia Front Oncol Oncology Secondary plasma cell leukemia (sPCL) is a rare form of aggressive plasma cell malignancy arising mostly at end-stage refractory multiple myeloma and consequently presenting limited therapeutic options. We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. Accordingly, BH3 profiling of 2 sPCL sensitive to BCLXL inhibition confirmed their high BCLXL primed profile. While targeting BCLXL using BH3 mimetics induces platelets on-target drug toxicity, the recent development of DT2216, a clinical-stage BCLXL proteolysis targeting chimera PROTAC compound, provides an alternative strategy to target BCLXL. Indeed, DT2216 specifically degrades BCLXL via VHL E3 ligase, without inducing thrombocytopenia. We demonstrated in human myeloma cell lines and sPCL that sensitivity to DT2216 strongly correlated with the sensitivity to A1155463. Interestingly, we showed that low doses of DT2216 (nM range) were sufficient to specifically degrade BCLXL after 48 hours of treatment, consistent with VHL expression, in all cell lines but irrespectively to DT2216 sensitivity. In myeloma cells, DT2216 induced apoptotic cell death and triggered BAX and BAK activation. In conclusion, our study demonstrated that patients with sPCL addicted to BCLXL, a small but a very challenging group, could potentially receive therapeutic benefit from DT2216. Clinical trials of DT2216 in this subset of sPCL patients are warranted. Frontiers Media S.A. 2023-07-17 /pmc/articles/PMC10393035/ /pubmed/37534243 http://dx.doi.org/10.3389/fonc.2023.1196005 Text en Copyright © 2023 Champion, Soler, Maïga, Bellanger, Pellat-Deceunynck, Talbot, Touzeau, Amiot and Gomez-Bougie https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Champion, Ophélie
Soler, Alana
Maïga, Sophie
Bellanger, Céline
Pellat-Deceunynck, Catherine
Talbot, Alexis
Touzeau, Cyrille
Amiot, Martine
Gomez-Bougie, Patricia
BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title_full BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title_fullStr BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title_full_unstemmed BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title_short BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival
title_sort bclxl protac degrader dt2216 targets secondary plasma cell leukemia addicted to bclxl for survival
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393035/
https://www.ncbi.nlm.nih.gov/pubmed/37534243
http://dx.doi.org/10.3389/fonc.2023.1196005
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