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

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

  • Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2116764119. doi: 10.1073/pnas.2116764119.
Daniel R Principe 1 2,  Rui Xiong 3,  Yangfeng Li 3,  Thao N D Pham 4,  Suneel D Kamath 5,  Oleksii Dubrovskyi 3,  Kiira Ratia 3,  Fei Huang 3,  Jiong Zhao 3,  Zhengnan Shen 3,  Dinesh Thummuri 6,  Zhou Daohong 6,  Patrick W Underwood 7,  Jose Trevino 8,  Hidayatullah G Munshi 4 9,  Gregory R J Thatcher 10,  Ajay Rana 11 9
Affiliations

Affiliations

  • 1 Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL 60612.
  • 2 Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612.
  • 3 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612.
  • 4 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
  • 5 Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44106.
  • 6 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610.
  • 7 Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610.
  • 8 Department of Surgery, Division of Surgical Oncology, Virginia Commonwealth University, Richmond, VA 23298.
  • 9 Jesse Brown VA Medical Center, Chicago, IL 60612.
  • 10 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85004 arana@uic.edu grjthatcher@arizona.edu.
  • 11 Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612; arana@uic.edu grjthatcher@arizona.edu.
PMID: 35064087 DOI: 10.1073/pnas.2116764119
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.

Keywords

BET inhibitor; KRAS; PD-1; pancreatic cancer.

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