Facing inevitable PARPis resistance: Mechanisms and therapeutic strategies for breast cancer treatment

Abstract

BRCA1/2 gene mutations, which result in a dysfunction of homologous recombination repair, have been discovered in at least 5% of breast cancer (BC) patients with the increase in BC incidence in recent years. PARP inhibitors (PARPis), the first drugs with clinical approval based on synthetic lethality, have been approved to treat BRCA1/2-mutant BC. However, as with other targeted drugs, PARPis drug resistance has become a significant obstacle in the application of PARPis. In this paper, we discuss the mechanism of PARPis, the clinical application of PARPis as monotherapy and the possible induced resistance mechanism. By exploring the resistance mechanism, we aimed to identify appropriate effective therapeutic techniques to overcome PARPis resistance and improve the efficacy of PARPis as well as to provide theoretical and experimental evidence for the clinical use of PARPis in BRCA1/2-mutant BC.

Biological clock regulation by the PER gene family: a new perspective on tumor development

“…However, factors such as intratumor heterogeneity, adaptive mutations, epigenetic alterations, and metabolic changes enable some cancer cells to withstand clinical doses of medications, thereby escalating the challenge of medication resistance in cancer treatment ( Vasan et al, 2019 ). Investigating the molecular mechanisms of drug resistance is crucial for improving therapeutic outcomes and introducing new treatment strategies ( Nussinov et al, 2021 ; Liu et al, 2023b ). Previous research revealed that oncogene-transformed mouse embryonic fibroblasts developed increased resistance to chemotherapeutic agents like methotrexate, gemcitabine, and etoposide, due to alterations of Per2 gene.…”