Br J Cancer: Targeted cell autophagy improves the production of PARP inhibitor resistance in breast cancer treatment

Breast cancer is one of the most common cancers among women in the world and the main cause of cancer-related deaths.
The International Agency for Research on Cancer estimates that there will be about 2 million new cases and 600,000 breast cancer-related deaths worldwide in 2018, and although the disease's detection techniques and treatment strategies have improved significantly over the past two decades, the development of chemotherapy resistance remains a major challenge in breast cancer treatment.
of the newer advances in the current breast cancer treatment strategy is the treatment strategy targeting PARP.
previous studies have shown that PARPs play a key role in a variety of cellular processes and are attractive and viable drug targets.
in breast cancer patients with BRCA mutations, PARP inhibitors (PARPis) show potential single-drug anti-tumor efficacy.
, however, the success of PARPi treatment is limited to a small percentage of breast cancer patients with BRCA1/2 mutations.
, the development of resistance in patients with BRCA mutant breast cancer can also lead to the failure of PARPi therapy.
and most patients with BRCA wild type (WT) breast cancer have intrinsic resistance to PARPi.
, there is an urgent need for a treatment strategy that can be widely used in breast cancer patients and those who are resistant to PARPi.
BRCA-WT breast cancer cells have an intrinsic drug-resistant cell autophagy mechanism for the treatment of his razorpani, which is an intracellular steady state mechanism that removes functional abnormalities and excess biom molecules and cytocytos devices.
previous studies have shown that inhibiting cell autophagy leads to a decrease in HR and an increase in NHEJ.
, however, it is not clear whether cell autophagy activation is associated with BRCA-WT breast cancer resistance to PARPi, and whether targeted cell autophagy is beneficial for PARPi treatment.
study aims to assess the role of cell autophagy in disease resistance and explore potential molecular mechanisms.
researchers evaluated autophagy formation and autophagy communication by detecting the expression levels of endogenetic LC3-II in breast cancer cells, as well as heterogeneic expressions EGFP-LC3 and mRFP-EGFP-LC3.
using CRISPR-Cas9 systems to knock out BECN1, ATG5, p62/SQSTM1, and LAMP1 to build autophagy-defective cells.
the response to PARPi in models of autophagy-capable and defective breast cancer cells and transplanted tumor mice.
inhibition of macrocellular autophagy led to a significant increase in cell autophagy levels in the BRCA-WT breast cancer cell line treated with talazoparib by researchers who treated PARPi.
autophagy-defective cells are sensitive to talazopani.
mouse models of transplanted tumors showed that targeted autophagy could work together to enhance the therapeutic effect of talaconi in BRCA1-WT breast cancer cells.
mechanism studies have shown that autophagy inhibition of chloroquine promotes harmful NHEJ-mediated DSB repair processes and ultimately leads to widespread genomic instability and cell-splitting disorders.
, the results show that cell autophagy can cause the production of PARAP inhibitor talapatani resistance.
inhibition of cell autophagy can improve the therapeutic effect of PARPi, and the findings also provide some theoretical basis for later clinical applications.