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

Daniel R. Principe, Rui Xiong, Yangfeng Li, Thao N.D. Pham, Suneel D. Kamath, Oleksii Dubrovskyi, Kiira Ratia, Fei Huang, Jiong Zhao, Zhengnan Shen, Dinesh Thummuri, Zhou Daohong, Patrick W. Underwood, Jose Trevino, Hidayatullah G. Munshi, Gregory R.J. Thatcher*, Ajay Rana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Article numbere2116764119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number4
DOIs
StatePublished - Jan 25 2022

Funding

ACKNOWLEDGMENTS. This work was supported by Veterans Affairs Merit Award I01BX004903 and Career Scientist Award IK6 BX004855 to A.R., Chicago Biomedical Consortium Accelerator Award and NIH UL1TR002003 provided via the UICentre to G.R.J.T. and R.X., NIH F30CA236031 and UIC Award for Graduate Research to D.R.P., NIH R01CA242003 and the Joseph and Ann Matella Fund for Pancreatic Cancer Research to J.G.T. and Z.D., and NIH R01CA217907, NIH R21CA255291, and Veterans Affairs Merit Award I01BX002922 to H.G.M. Per the funding policy of the US Department of Veterans Affairs, we are required to state that these contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Keywords

  • BET inhibitor
  • KRAS
  • PD-1
  • Pancreatic cancer

ASJC Scopus subject areas

  • General

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  • CBP bromodomain complexed with YF2-23

    Li, Y. (Contributor), Zhao, J. (Contributor), Gutgesell, L. M. (Contributor), Shen, Z. (Contributor), Ratia, K. (Contributor), Dye, K. (Contributor), Dubrovskyi, O. (Contributor), Zhao, H. (Contributor), Huang, F. (Contributor), Tonetti, D. A. (Contributor), Thatcher, G. R. J. (Contributor), Xiong, R. (Contributor), Principe, D. R. (Contributor), Pham, T. N. D. (Contributor), Kamath, S. D. (Contributor), Thummuri, D. (Contributor), Daohong, Z. (Contributor), Underwood, P. W. (Contributor), Trevino, J. (Contributor), Munshi, H. G. (Contributor) & Rana, A. (Contributor), Protein Data Bank (PDB), Sep 1 2021

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