XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer-Reference-Cited by-同舟云学术

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

Published:2022-01-21 Issue:4 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Principe Daniel R.¹²^ORCID,Xiong Rui³^ORCID,Li Yangfeng³,Pham Thao N. D.⁴^ORCID,Kamath Suneel D.⁵,Dubrovskyi Oleksii³,Ratia Kiira³,Huang Fei³^ORCID,Zhao Jiong³,Shen Zhengnan³^ORCID,Thummuri Dinesh⁶,Daohong Zhou⁶,Underwood Patrick W.⁷,Trevino Jose⁸,Munshi Hidayatullah G.⁴⁹,Thatcher Gregory R. J.¹⁰^ORCID,Rana Ajay²⁹^ORCID

Affiliation:

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

Abstract

SignificanceThere 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.

Funder

U.S. Department of Veterans Affairs

Chicago Biomedical Consortium Accelerator Award and NIH

HHS | NIH | National Cancer Institute

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2116764119

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