Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy

Jacob Cuyler; Pranav Murthy; Neal G Spada; Terence F McGuire; Michael T Lotze; Xiang-Qun Xie

doi:10.1016/j.drudis.2021.09.011

Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy

Drug Discov Today. 2022 Jan;27(1):362-370. doi: 10.1016/j.drudis.2021.09.011. Epub 2021 Sep 27.

Authors

Jacob Cuyler¹, Pranav Murthy², Neal G Spada³, Terence F McGuire¹, Michael T Lotze⁴, Xiang-Qun Xie⁵

Affiliations

¹ Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
² Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
³ Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
⁴ Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Immunology and Bioengineering, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: lotzemt@upmc.edu.
⁵ Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: xix15@pitt.edu.

PMID: 34592447
DOI: 10.1016/j.drudis.2021.09.011

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by heightened autophagy and systemic immune dysfunction. Modest improvements in clinical outcomes have been demonstrated in completed clinical trials targeting autophagy with combination hydroxychloroquine (HCQ) and chemotherapy. Recent mechanistic insights into the role of autophagy-dependent immune evasion have prompted the need for more precise and druggable targets of autophagy inhibition. Sequestosome-1 (SQSTM-1) is a multidomain scaffold protein with well-established roles in autophagy, tumor necrosis factor alpha (TNFα)- and NF-κB-related signaling pathways. SQSTM1 overexpression is frequently observed in PDAC, correlating with clinical stage and outcome. Given the unique molecular structure of SQSTM-1 and its diverse activity, identifying means of limiting SQSTM-1-dependent autophagy to promote an effective immune response in PDAC could be a promising treatment strategy.

Keywords: Autophagy; Drug discovery; Hydroxychloroquine; Pancreatic cancer; Sequestome-1; p62.

Publication types

Review

MeSH terms

Autophagy* / drug effects
Autophagy* / immunology
Drug Discovery / methods*
Humans
Molecular Targeted Therapy / methods
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / metabolism
Sequestosome-1 Protein / metabolism*
Signal Transduction / drug effects

Substances

SQSTM1 protein, human
Sequestosome-1 Protein