A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer
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| Publication Date: | 2025 |
| Other Authors: | , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | https://hdl.handle.net/1822/95558 |
Summary: | The online version contains supplementary material available at: https://doi.org/10.1038/s41467-022-32178-3 |
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A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancerThe online version contains supplementary material available at: https://doi.org/10.1038/s41467-022-32178-3Background Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA. Methods In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay. Results The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy. Conclusion These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.This research received financial support from national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through projects 2022.05718.PTDC, https://doi.org/10.54499/LA/P/0008/2020, https://doi.org/10.54499/UIDP/50006/2020, https://doi.org/10.54499/UIDP/50006/2020 (LAQV/REQUIMTE), and https://doi.org/10.54499/UIDB/04469/2020 (CEB/UMinho), and from BBIT-Therapeutics, Lda. We thank FCT/MCTES for the fellowships 2020.04613.BD (J.C.) and 2020.06020.BD (F.B.). J.M. thanks Liga Portuguesa Contra o Cancro – Núcleo Regional do Norte. VC is supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG No 288801) and by National Cancer Institute (NHI; HHSN26100008).info:eu-repo/semantics/publishedVersionSpringer NatureUniversidade do MinhoCalheiros, JulianaSilva, RitaBarbosa, FilipaMorais, JoãoMoura, Sara ReisAlmeida, SofiaFiorini, ElenaMulhovo, SilvaAguiar, Tatiana QuintaWang, TaoRicardo, SaraAlmeida, Maria InêsDomingues, LucíliaMelo, Sónia A.Corbo, VincenzoFerreira, Maria-José U.Saraiva, Lucília2025-04-242025-04-24T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/95558engCalheiros, J., Silva, R., Barbosa, F. et al. A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer. J Exp Clin Cancer Res 44, 129 (2025). https://doi.org/10.1186/s13046-025-03389-50392-907810.1186/s13046-025-03389-5https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03389-5info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-05-10T01:17:28Zoai:repositorium.sdum.uminho.pt:1822/95558Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T07:05:47.408784Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| title |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| spellingShingle |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer Calheiros, Juliana |
| title_short |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| title_full |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| title_fullStr |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| title_full_unstemmed |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| title_sort |
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer |
| author |
Calheiros, Juliana |
| author_facet |
Calheiros, Juliana Silva, Rita Barbosa, Filipa Morais, João Moura, Sara Reis Almeida, Sofia Fiorini, Elena Mulhovo, Silva Aguiar, Tatiana Quinta Wang, Tao Ricardo, Sara Almeida, Maria Inês Domingues, Lucília Melo, Sónia A. Corbo, Vincenzo Ferreira, Maria-José U. Saraiva, Lucília |
| author_role |
author |
| author2 |
Silva, Rita Barbosa, Filipa Morais, João Moura, Sara Reis Almeida, Sofia Fiorini, Elena Mulhovo, Silva Aguiar, Tatiana Quinta Wang, Tao Ricardo, Sara Almeida, Maria Inês Domingues, Lucília Melo, Sónia A. Corbo, Vincenzo Ferreira, Maria-José U. Saraiva, Lucília |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade do Minho |
| dc.contributor.author.fl_str_mv |
Calheiros, Juliana Silva, Rita Barbosa, Filipa Morais, João Moura, Sara Reis Almeida, Sofia Fiorini, Elena Mulhovo, Silva Aguiar, Tatiana Quinta Wang, Tao Ricardo, Sara Almeida, Maria Inês Domingues, Lucília Melo, Sónia A. Corbo, Vincenzo Ferreira, Maria-José U. Saraiva, Lucília |
| description |
The online version contains supplementary material available at: https://doi.org/10.1038/s41467-022-32178-3 |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025-04-24 2025-04-24T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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https://hdl.handle.net/1822/95558 |
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https://hdl.handle.net/1822/95558 |
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eng |
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eng |
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Calheiros, J., Silva, R., Barbosa, F. et al. A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer. J Exp Clin Cancer Res 44, 129 (2025). https://doi.org/10.1186/s13046-025-03389-5 0392-9078 10.1186/s13046-025-03389-5 https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03389-5 |
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openAccess |
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Springer Nature |
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Springer Nature |
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