XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer

Abstract

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.

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

“…JQ1 combined with PD-1 blockade enhances the anti-tumor response in Kras-mutant lung cancer by reducing the T-reg and increasing T-cell infiltration with T-helper type 1 cytokine [ 75 ]. In pancreatic cancer, a dual inhibitor of BET proteins and HATs suppress KRAS/MAPK signaling and augment PDL1 blockade through recruitment of cytotoxic T-cell [ 76 ]. Several BET bromodomain inhibitors are vigorously investigated in clinical trials of anticancer treatment and only one phase I study is evaluating the combination therapy of BET inhibitor and immune checkpoint inhibitor [ 77 , 78 ].…”

Leukocyte subtyping predicts for treatment failure and poor survival in anal squamous cell carcinoma

“…Results were arranged by the Tukey method. Time-to-event survival data was evaluated via the Kaplan-Meier method [21,22]. Data were considered significant at p < 0.05 unless otherwise noted.…”

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition

“…For BRCA and PALB2 , germline mutation frequencies are estimated to be present in 5–9% of patients [ 29 , 30 , 31 , 32 ]. When analyzing publicly available datasets of PDAC patients ( N = 741) as described previously [ 33 , 34 , 35 , 36 ], the frequency of these mutations was far lower, with a composite mutation rate of 2.97% for ATM , 1.08% for BRCA1 , 1.48% for BRCA2 , and 0.54% for PALB2 ( Table 1 ). While several of these mutations are known to be oncogenic, presumed to confer loss-of-function and support tumorigenesis, several are poorly described and the impact on HR is unknown ( Table 2 ).…”

“…Similar results were observed using the BET inhibitor INCB054329 in ovarian cancer cells [ 84 ], further supporting the potential of combined BET and PARP inhibition in solid tumors. As emerging data also suggest that BET inhibitors can cooperate with immune checkpoint inhibition in PDAC [ 36 , 85 ], the combination of BET, PARP, and immune checkpoint inhibitors also warrants consideration.…”