ArticleJournal of experimental & clinical cancer research : CR2025
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- NUP93 facilitates the nuclear import of SOX2 to activate G3BP1 transcription and impairs gemcitabine response in pancreatic cancer.Cell death & disease · 2026Article
- Identification and characterization of MARCO-expressing tumor-associated macrophages in pancreatic ductal adenocarcinoma with pan-cancer relevance.NPJ precision oncology · 2026Article
- N-Alkylated Monoterpene Indole Alkaloid Derivatives as Chemotherapy Adjuvants That Overcome P-glycoprotein-Mediated Multidrug Resistance in Cancer Cells, Spheroids and Patient-Derived Colorectal Cancer Organoids.Drug design, development and therapy · 2026Article
- Article
- Chronic stress promotes pancreatic ductal adenocarcinoma progression via complement C5a-recruited myeloid-derived suppressor cells.Cancer immunology, immunotherapy : CII · 2025Article
- BARD1: A Friend or Foe in Pancreatic Ductal Adenocarcinoma?International journal of molecular sciences · 2025Review
- Role of m6A RNA methylation regulators in pancreatic cancer: interactions and potential implications.Cancer cell international · 2025Review
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17 authors.
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Abstract
backgroundPancreatic 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.
methodsIn 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.
resultsThe 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.
conclusionThese findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.
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