Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma In Situ Induces Synthetic Lethality and Chemoprevention

Abstract

Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and preinvasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis. XRCC1-deficient DCIS were aggressive and associated with increased risk of local recurrence. Human invasive breast cancers deficient in XRCC1 and expres-sing high PARP1 levels also manifested aggressive features and poor outcome. The PARP1 inhibitor olaparib was synthetically lethal in XRCC1-deficient DCIS and invasive breast cancer cells. We conclude that targeting PARP1 is an attractive strategy for synthetic lethality and chemoprevention in XRCC1-deficient breast cancers, including preinvasive DCIS.Significance: These findings show that loss of XRCC1, which is associated with more malignant DCIS, can be exploited by PARP inhibition, suggesting its application as a promising therapeutic and chemoprevention strategy in XRCC1-deficient tumor cells. Cancer Res; 78(24); 6818-27. Ó2018 AACR.

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

“…Examining DNA repair defects in both preclinical models and patients is essential for evaluating the efficacy of therapeutic agents. Several studies have noted deficiency in XRCC1 in breast cancers and proposed deficiency in XRCC1 and defects in BER as targets for therapeutic intervention [16, 18, 19]. However, characterization of BER defects, particularly those linked to XRCC1 in breast cancer has been lacking.…”

“…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].…”

“…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]. However, the mechanism of sensitization of XRCC1-deficient cancer cells to PARPi therapy remains unclear.…”

“…TNBC may be aggressive and unresponsive to current treatments that target estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, TNBCs have a high prevalence of DNA repair defects, though not always associated with mutations in the BRCA1/2 genes [1, 16–18, 22].…”

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

“…Even in the TOPARP-B trial, a phase II randomized trial of PARPi olaparib for metastatic castration resistant prostate cancers (mCRPC) with DDR alterations, which used a panel of 133 genes, some tumors that are considered DDR-deficient do not respond to PARP inhibition, whereas others that lack DDR mutations do [15,16]. This lack of predictive capacity can be associated with the complexity and redundancy of DDR pathways or with the restoration of HRR function through various resistance mechanisms [14,[16][17][18][19][20].…”