Targeting Transcription-Replication Conflicts using G-quadruplexes stabilizers in Multiple Myeloma
Laure Dutrieux
(1)
,
Sara Ovejero
(2, 1)
,
Antoine Guillemin
(1)
,
Leriem Zellagui
(1)
,
Elke de Bruyne
(3)
,
Catharina Muylaert
(3)
,
Lien van Hemelrijck
(3)
,
Yea-Lih Lin
(1)
,
Elle Loughran
(4, 5)
,
Armelle Choquet
(6)
,
Talha Magat
(7)
,
Soumya Bouchouika
(1, 7)
,
Caroline Bret
(1, 2, 8)
,
Guilhem Requirand
(1, 9)
,
Nicolas Robert
(10)
,
Laure Vincent
(10)
,
Guillaume Cartron
(10)
,
Charles Herbaux
(2, 1)
,
Raphaël Rodriguez
(11)
,
Michel Cogne
(12, 13, 14)
,
Eric Rivals
(5)
,
Jean-Christophe Andrau
(7)
,
Alexandre David
(8)
,
Philippe Pasero
(1)
,
Jérôme Moreaux
(1, 2, 15, 16)
1
IGH -
Institut de génétique humaine
2 CHU Montpellier = Montpellier University Hospital
3 VUB - Vrije Universiteit Brussel [Bruxelles]
4 Smurfit Institute of Genetics
5 LIRMM | MAB - Méthodes et Algorithmes pour la Bioinformatique
6 IGF - Institut de Génomique Fonctionnelle
7 IGMM - Institut de Génétique Moléculaire de Montpellier
8 UM - Université de Montpellier
9 Pôle Biologie-Pathologie [CHRU Montpellier]
10 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
11 CBMCT - UMR 3666 / U1143 - Chimie biologique des membranes et ciblage thérapeutique
12 MOBIDIC - Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer
13 EFS Bretagne - Etablissement français du sang [Rennes]
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
15 INSERM - Institut National de la Santé et de la Recherche Médicale
16 IUF - Institut universitaire de France
2 CHU Montpellier = Montpellier University Hospital
3 VUB - Vrije Universiteit Brussel [Bruxelles]
4 Smurfit Institute of Genetics
5 LIRMM | MAB - Méthodes et Algorithmes pour la Bioinformatique
6 IGF - Institut de Génomique Fonctionnelle
7 IGMM - Institut de Génétique Moléculaire de Montpellier
8 UM - Université de Montpellier
9 Pôle Biologie-Pathologie [CHRU Montpellier]
10 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
11 CBMCT - UMR 3666 / U1143 - Chimie biologique des membranes et ciblage thérapeutique
12 MOBIDIC - Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer
13 EFS Bretagne - Etablissement français du sang [Rennes]
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
15 INSERM - Institut National de la Santé et de la Recherche Médicale
16 IUF - Institut universitaire de France
Sara Ovejero
- Function : Author
- PersonId : 1416462
- ORCID : 0000-0002-8354-856X
Elke de Bruyne
- Function : Author
- PersonId : 1100439
- ORCID : 0000-0003-4012-4617
Catharina Muylaert
- Function : Author
- PersonId : 1499382
- ORCID : 0000-0002-2347-9152
Lien van Hemelrijck
- Function : Author
- PersonId : 1499383
- ORCID : 0000-0002-7452-4283
Yea-Lih Lin
- Function : Author
- PersonId : 742009
- IdHAL : yea-lih-lin
- ORCID : 0000-0003-4063-0771
Elle Loughran
- Function : Author
- PersonId : 1499225
- ORCID : 0000-0001-7328-0929
Armelle Choquet
- Function : Author
- PersonId : 1179705
- ORCID : 0000-0002-6959-9387
Talha Magat
- Function : Author
- PersonId : 1499226
- ORCID : 0009-0006-4250-628X
Soumya Bouchouika
- Function : Author
- PersonId : 1498134
- ORCID : 0009-0004-5106-4183
Caroline Bret
- Function : Author
- PersonId : 1108441
- ORCID : 0000-0003-4784-2566
Guilhem Requirand
- Function : Author
- PersonId : 1132355
Nicolas Robert
- Function : Author
- PersonId : 1132354
- ORCID : 0009-0009-2595-6168
Laure Vincent
- Function : Author
- PersonId : 1096565
Guillaume Cartron
- Function : Author
- PersonId : 759743
- ORCID : 0000-0003-0659-9635
- IdRef : 075137119
Charles Herbaux
- Function : Author
- PersonId : 772312
- ORCID : 0000-0003-4910-476X
- IdRef : 144856395
Raphaël Rodriguez
- Function : Author
- PersonId : 771479
- ORCID : 0000-0001-7668-446X
- IdRef : 094813035
Michel Cogne
- Function : Author
- PersonId : 792647
- ORCID : 0000-0002-8519-4427
- IdRef : 059176474
Eric Rivals
- Function : Author
- PersonId : 2002
- IdHAL : eric-rivals
- ORCID : 0000-0003-3791-3973
- IdRef : 118021850
Jean-Christophe Andrau
- Function : Author
- PersonId : 740768
- IdHAL : jean-christophe-andrau
- ORCID : 0000-0003-0203-8507
- IdRef : 153245352
Alexandre David
- Function : Author
- PersonId : 1499621
- IdHAL : sebastien-cacchia
- IdRef : 126063389
Philippe Pasero
- Function : Author
- PersonId : 904163
- ORCID : 0000-0001-5891-0822
- IdRef : 113762143
Jérôme Moreaux
- Function : Author
- PersonId : 982751
- IdHAL : jerome-moreaux
- ORCID : 0000-0002-5717-3207
Abstract
Replication stress exerts an important role in fueling genomic instability characterizing Multiple Myeloma (MM) evolution, and is a leading cause of drug resistance. Normal and malignant plasma cells (PCs) are associated with a high transcriptional stress due to the huge production of immunoglobulins. Transcription-Replication Conflicts (TRCs) arising from collisions between replication and transcription machineries can promote tumor progression and represent an Achilles’ heel to cancer cells. We reported a gene signature related to TRCs management (TRC score) overexpressed in malignant versus normal PCs. High TRC score identified MM patients with a poor prognosis who could benefit from a TRC-enhancing therapy, in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Here, we investigated the therapeutic interest of increasing TRCs to target specifically malignant PCs using the G-quadruplex (G4) stabilizer Pyridostatin (PDS). PDS exerted significant toxicity in MM cell lines and primary MM cells, induced DNA damage, cell cycle arrest and apoptosis. Importantly, primary myeloma cells are significantly more sensitive to PDS treatment than normal bone marrow cells. Moreover, PDS improved the efficacy of MM treatments such as melphalan and HDAC or BRD inhibitors. Thus, our study shows that G4 stabilizers could be used to specifically target MM cells that exhibit concomitant replication stress and a high level of transcription, through the increase of TRCs. These molecules could be used to increase the efficacy of other treatments including melphalan, HDAC inhibitors, and BRD inhibitors.