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Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy
Jacob Cuyler1, Pranav Murthy2, Neal G Spada3
1Department 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.
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.
Insights
Pancreatic cancer cells use autophagy to evade immune attack. Targeting Sequestosome-1 (SQSTM-1) may block this process, enhancing immune response and improving treatment outcomes for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits increased autophagy and immune dysfunction.
- Current therapies targeting autophagy, like hydroxychloroquine (HCQ) and chemotherapy, show limited clinical benefit.
- Autophagy plays a key role in immune evasion within the PDAC tumor microenvironment.
Purpose of the Study:
- To investigate Sequestosome-1 (SQSTM-1) as a potential therapeutic target in PDAC.
- To explore the role of SQSTM-1 in autophagy-dependent immune evasion.
- To identify strategies for limiting SQSTM-1 activity to enhance anti-tumor immunity.
Main Methods:
- Analysis of SQSTM1 expression in PDAC patient samples.
- Examination of SQSTM-1's role in autophagy pathways.
- Investigation of SQSTM-1's involvement in TNFα and NF-κB signaling.
Main Results:
- SQSTM1 is overexpressed in PDAC, correlating with advanced disease and poorer outcomes.
- SQSTM-1 is a crucial scaffold protein involved in autophagy regulation.
- SQSTM-1 contributes to immune evasion mechanisms in PDAC.
Conclusions:
- SQSTM-1 represents a promising therapeutic target for PDAC.
- Inhibiting SQSTM-1-mediated autophagy could restore immune surveillance.
- Targeting SQSTM-1 may lead to more effective immunotherapies for pancreatic cancer.
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