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Proteomic Analysis Identifies p62/SQSTM1 as a Critical Player in PARP Inhibitor Resistance
Mohammed Hafiz Uddin1, Jun-Ying Zhou1, Julio Pimentel2
1Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States.
Frontiers in Oncology
|July 18, 2022
Summary
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) resistance in breast cancer may be overcome by targeting autophagy. Stimulating autophagy with drugs like rapamycin can re-sensitize resistant cells to PARPis, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are vital for treating BRCA-mutated breast cancer.
- Acquired resistance to PARPis is a significant clinical challenge, limiting long-term patient survival.
- The precise mechanisms driving PARPi resistance remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying acquired resistance to PARP inhibitors (PARPis) in breast cancer.
- To identify potential therapeutic strategies to overcome PARPi resistance.
Main Methods:
- Established olaparib-resistant SUM159 and MDA468 cell lines through chronic drug exposure.
- Utilized unbiased proteomics to compare protein expression between sensitive and resistant cells.
- Performed Ingenuity Pathway Analysis (IPA) to identify altered signaling pathways.
- Assessed the sensitivity of resistant cells to cisplatin and the effect of autophagy inducers (rapamycin, everolimus) on PARPi sensitivity.
Main Results:
- Olaparib-resistant cells exhibited defects in PARPi-induced DNA damage but remained sensitive to cisplatin.
- Proteomic analysis identified 107 differentially expressed proteins, with significant alterations in mTOR and ubiquitin pathways.
- p62/SQSTM1 (p62), a key autophagy-related protein, was significantly downregulated in olaparib-resistant cells.
- Autophagy inducers rapamycin and everolimus synergistically sensitized olaparib-resistant cells to olaparib.
- p62 protein expression correlated with better overall survival in estrogen receptor-negative breast cancer.
Conclusions:
- Acquired resistance to PARPis in triple-negative breast cancer (TNBC) is associated with hyperactivated autophagy.
- Pharmacological stimulation of excessive autophagy presents a promising strategy to overcome PARPi resistance.
- Targeting autophagy pathways, potentially through p62 modulation, could restore sensitivity to PARPis and improve patient outcomes.
