Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in tumors for personalized cancer therapy.

Abstract

1014 Background: XRCC1 is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. XRCC1 deficiency promotes genomic instability and may increase cancer risk. Methods: We evaluated XRCC1 immunohistochemically in early stage breast (n=2046), ovarian (n=157), gastric (n=140), colorectal (n=250) and pancreaticobiliary cancers (n=240). Pre-clinically, we evaluated a panel of XRCC1 deficient and proficient Chinese hamster ovary and human cancer cell lines. Double strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs (NU7441) and ATR (NU6027) were evaluated for synthetic lethality and cisplatin alone or in combination with DSB inhibitors for chemopotentiation. Results: In breast cancer,XRCC1 loss (16%) was associated with higher grade (p<0.0001), loss of hormone receptors (p<0.0001), presence of triple negative (p<0.0001) and basal like phenotypes (p=0.001). Loss of XRCC1 was associated with a 2-fold increase in risk of death and metastasis (p<0.0001) and independently with poor outcome (p<0.0001). In ovarian cancer, XRCC1 was positive in 44% of tumour and was significantly associated with higher stage (p=0.001), clear/endometroid type (p=0.015) and sub-optimal debulking (p=0.004). XRCC1 positive tumours were more resistant to platinum chemotherapy (p=0.0001). XRCC1 positivity conferred a 2 fold increase of risk of death (p=0.002) and independently associated with poor survival (p=0.002). In gastric cancers, XRCC1 was positive in 37% of tumours. This was significantly associated with high stage disease (p=0.001) and poor survival (p=0.001). Pre-clinically, KU55933, NU7441 and NU6027 were synthetically lethal in XRCC1 deficient compared to proficient cells as evidenced by DSB accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells were hypersensitive to cisplatin which was enhanced by DSB repair inhibitors compared to in proficient cells. Conclusions: This is the largest study to confirm the clinical significance of XRCC1 expression in solid tumours. XRCC1 deficiency in human tumours may be suitable for synthetic lethality application and exploited for cisplatin chemotherapy potentiation.