The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models

Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with hom...

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Autores: Herencia-Ropero, Andrea|||0009-0002-9448-1484, Llop Guevara, Alba|||0000-0002-7913-9472, Staniszewska, Anna D., Domènech-Vivó, Joanna|||0000-0002-8049-7488, García-Galea, Eduardo|||0000-0003-4699-0786, Moles-Fernández, Alejandro|||0000-0003-0252-6084, Pedretti, Flaminia, Domènech, Heura, Rodríguez, Olga|||0000-0002-0123-9975, Guzmán, Marta|||0000-0002-0924-9887, Arenas, Enrique, Verdaguer, Helena|||0000-0001-6163-382X, Calero-Nieto, Fernando|||0000-0003-3358-8253, Talbot, Sara, Tobalina, Luis, Leo, Elisabetta, Lau, Alan|||0000-0003-1055-9812, Nuciforo, Paolo|||0000-0003-1380-0990, Dienstmann, Rodrigo|||0000-0001-5997-318X, Macarulla Mercadé, Teresa|||0000-0002-5856-4082, Arribas, Joaquín V.|||0000-0002-0504-0664, Diez, Orland|||0000-0001-7339-0570, Gutiérrez-Enríquez, Sara|||0000-0002-1711-6101, Forment, Josep V.|||0000-0002-7797-2583, O'Connor, Mark J.|||0000-0003-1823-625X, Albertella, Mark Robert, Balmaña Gelpí, Judith|||0000-0002-0762-6415, Serra, Violeta|||0000-0001-6620-1065
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:310572
Acceso en línea:https://ddd.uab.cat/record/310572
https://dx.doi.org/urn:doi:10.1186/s13073-024-01370-z
Access Level:acceso abierto
Palabra clave:Antitumor activity
BRCA1/2
Breast cancer
DNA damaging agent
HRD
Homologous recombination deficiency
PARP inhibitors
PARP1 selective
RAD51
Targeted therapy
Descripción
Sumario:Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. Methods: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. Results: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (.

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