Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug
Menée à l'aide de lignées cellulaires, d'organoïdes et de modèles murins d'adénocarcinome canalaire du pancréas exprimant fortement le facteur de transcription NRF2, cette étude met en évidence l'intérêt thérapeutique de C29h, un promédicament spécifiquement activé par l'enzyme NAD(P)H:quinone oxydoréductase-1 dont l'expression est induite par NRF2
NRF2 activation is associated with resistance to oxidant-producing chemo- and radiotherapies, as well as enhanced pancreatic ductal adenocarcinoma (PDAC) growth and metastatic spread, and poor patient survival. Here, we show that NRF2high PDAC can be selectively controlled by a prodrug, C29h, that is specifically activated by the NRF2-inducible enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1). In addition to targeted therapy of this PDAC subset, C29h and related NQO1-activatable prodrugs may augment responses to standard-of-care drugs while reducing the systemic toxicity of chemotherapy. Given its greater efficacy in immunocompetent hosts, we propose that C29h may also augment the response to immunotherapy. Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2high PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1high human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKKα-deficient KrasG12D/IkkαΔPEC mice in which NRF2 is strongly activated, immunocompromised Nu/Nu mice orthotopically transplanted with human PDAC cells and C57BL/6n and NOD/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8+ T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2high PDAC.
Proceedings of the National Academy of Sciences , article en libre accès, 2026