2. Academic Validation
  3. Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

  • Oncogene. 2017 Aug 17;36(33):4719-4731. doi: 10.1038/onc.2017.41.
W Lu 1 2,  F Cheng 3,  W Yan 1,  X Li 1,  X Yao 1,  W Song 4,  M Liu 2,  X Shen 1 5,  H Jiang 1 5,  J Chen 4 6 7 8,  J Li 1,  J Huang 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 3 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
  • 4 Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 5 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China.
  • 6 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 7 Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 8 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
PMID: 28394340 DOI: 10.1038/onc.2017.41
Abstract

TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in Cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted Cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung Cancer (NSCLC) cell cycle arrest and Apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of Reactive Oxygen Species and DNA damage by HL001 contribute to p53 stabilization. Surprisingly, HL001 selectively suppresses tumor growth in p53 wild-type NSCLC harboring Arg72 homozygous alleles (p53-72R) through disrupting interaction between MDM2 and p53-72R in a CypA-dependent manner. Moreover, combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model. Collectively, this study demonstrates that pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.

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