Targeting BRCA1‐BER deficient breast cancer by ATM or DNA‐PKcs blockade either alone or in combination with cisplatin for personalized therapy

Abstract

BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n = 1602 sporadic and n = 50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p < 0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps < 0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy.

Aberrant DNA Double-strand Break Repair Threads in Breast Carcinoma: Orchestrating Genomic Insult Survival

“…It has been suggested that BRCA1-BER-deficient cells may show improved sensitivity to treatment when cisplatin is concomitantly administered with ATM and DNA-PKcs inhibitors. These types of drugs/inhibitors combination treatment options will provide better options for personalized therapy 15,62. In preliminary findings, a new class of drugs, an imidazopyridine derivative, targeting the DNA damage response pathway was administered in combination with Doxorubicin to assess cytotoxicity in breast carcinoma.…”

Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

“…Patient demographics are summarized in Supplementary Table S3. This is a well-characterized series of patients with long-term follow-up that have been investigated in a wide range of biomarker studies (12)(13)(14)(15)(16)(17)(18)(19)(20). All patients were treated in a uniform way in a single institution with standard surgery (mastectomy or wide local excision) with radiotherapy.…”

“…The TMAs were immunohistochemically profiled for BLM and other biologic antibodies (Supplementary Table S4) as previously described (12)(13)(14)(15)(16)(17)(18)(19)(20). Immunohistochemical (IHC) staining was performed using the Thermo Scientific Shandon Sequenza chamber system (REF: 72110017), in combination with the Novolink Max Polymer Detection System (RE7280-K: 1,250 tests), and the Leica Bond Primary Antibody Diluent (AR9352), each used according to the manufacturer's instructions (Leica Microsystems).…”

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

“…XRCC1 is ubiquitously expressed in normal tissues, but low levels of XRCC1 causing impaired BER may occur in terminally differentiated muscle cells and neurons [14, 15]. Variations in XRCC1 expression levels have been observed in breast cancer patient samples [16–18], and breast cancers with low expression levels of XRCC1 have been proposed as targets for PARPi treatment [16–19]. Defects in BER and XRCC1 may sensitize breast cancer cells to PARPi, similar to homologous recombination and BRCA1/2 defects [16, 18, 20, 21].…”