XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer
Menée à l'aide d'échantillons biopsiques prélevés sur 3 patients atteints d'un adénocarcinome canalaire du pancréas et menée à l'aide de deux modèles murins transgéniques, cette étude met en évidence l'intérêt thérapeutique de la molécule XP-524, un inhibiteur de la protéine BET BRD4 et de l'histone acétyltransférase EP300
There are currently no effective treatments for pancreatic ductal adenocarcinoma (PDAC), which displays widespread resistance to chemotherapy, radiation therapy, and immunotherapy. Here, we demonstrate that the multispecificity BET/EP300 inhibitor XP-524 has pronounced single-agent efficacy in vitro, in vivo, and in ex vivo human PDAC slice cultures, functioning in part by attenuating oncogenic KRAS signaling. In vivo XP-524 led to extensive reprogramming of the pancreatic tumor microenvironment, sensitizing murine carcinoma to immune checkpoint inhibition and further extending survival. Given the urgent need for therapeutic approaches in PDAC, the combination of XP-524 and immune checkpoint inhibition warrants additional exploration.Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti–PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.