Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Abstract

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

Multi-omic characterization of ILC and ILC-like cell lines as part of ILC cell line encyclopedia (ICLE) defines new models to study potential biomarkers and explore therapeutic opportunities

“…With this information, researchers can choose suitable ILC/ILC-like cell lines based on the deregulated pathway on interest. Notably, each of these pathways is druggable using systematic or targeted agents e.g., endocrine therapies to against hormone signaling, HER2 and PI3K inhibitors against RTK signaling 98,99 , chemotherapy and CDK4/6 inhibitors 54 for inhibiting cell cycle and proliferation and PARP inhibitors against tumors with homologous repair defects (HRD) 100 . Knowledge of these deregulated pathways in ILC/ILC-like cell lines will be critical for developing precision therapies for human-ILC disease.…”

DNA damage targeted therapy for advanced breast cancer

“…This comprehensive analysis specifically examined mutations in genes related to HRR genes, excluding BRCA1/2 from consideration. This analysis demonstrated that the occurrence of mutations in HRR genes remained relatively infrequent, comprising less than 1% of cases, with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence rates [24].…”

FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism

“…Nevertheless, increasing evidence has shown that PARPi resistance is still present in patients without BRCA1/2 mutations; thus, massive efforts have been made to investigate other potential markers for predicting the sensitivity of PARPis. Among these genes, those involved in HR pathways, such as RAD51, ATM and ATR, are the most explored candidates [ 39 , 40 ]. Preclinical studies have shown that the expression of these genes is positively correlated with sensitivity to PARPi treatment and can enhance the response to PARPi treatment in cancer cells.…”