ArticleFrontiers in oncology2022
Proteomic Analysis Identifies p62/SQSTM1 as a Critical Player in PARP Inhibitor Resistance.
Article in Frontiers in oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
4 citing papers in PubMed, 7 citations in OpenAlex.
- Nucleophagy removes cytotoxic trapped PARP1.Nature cell biology · 2026Article
- Targeting Autophagy to Overcome Chemoresistance and Immune Resistance in Triple-Negative Breast Cancer.Cancers · 2026Review
- Autophagy and cancer therapy.Cancer letters · 2024Review
- Is autophagy induction by PARP inhibitors a target for therapeutic benefit?Oncology research · 2022Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently being used for treating breast cancer patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic diseases. Despite durable responses, almost all patients receiving PARPis ultimately develop resistance and succumb to their illness, but the mechanism of PARPi resistance is not fully understood. To better understand the mechanism of PARPi resistance, we established two olaparib-resistant SUM159 and MDA468 cells by chronically exposing olaparib-sensitive SUM159 and MDA468 cells to olaparib. Olaparib-resistant SUM159 and MDA468 cells displayed 5-fold and 7-fold more resistance over their corresponding counterparts. Despite defects in PARPi-induced DNA damage, these olaparib-resistant cells are sensitive to cisplatin-induced cell death. Using an unbiased proteomic approach, we identified 6 447 proteins, of which 107 proteins were differentially expressed between olaparib-sensitive and -resistant cells. Ingenuity pathway analysis (IPA) revealed a number of pathways that are significantly altered, including mTOR and ubiquitin pathways. Among these differentially expressed proteins, p62/SQSTM1 (thereafter p62), a scaffold protein, plays a critical role in binding to and delivering the ubiquitinated proteins to the autophagosome membrane for autophagic degradation, was significantly downregulated in olaparib-resistant cells. We found that autophagy inducers rapamycin and everolimus synergistically sensitize olaparib-resistant cells to olaparib. Moreover, p62 protein expression was correlated with better overall survival in estrogen receptor-negative breast cancer. Thus, these findings suggest that PARPi-sensitive TNBC cells hyperactivate autophagy as they develop acquired resistance and that pharmacological stimulation of excessive autophagy could lead to cell death and thus overcome PARPi resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.