Accepted Abstracts: J Cancer Sci Ther
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and effective treatment of HCC is of urgent need. In HCC, genomic instability is one of major hallmarks, especially in the tumors at the late stage and metastatic tumors. Thus, we seek to explore if targeting genomic instability and defective DNA repair can effectively inhibit HCC growth. BRIT1/MCPH1 is a recently identified key DNA damage and repair proteins. Recently, we identified that BRIT1 is aberrantly expressed in ~25% of HCC samples. In these samples, the locus of BRIT2 gene showed notable loss of heterogeneity (nearly 50%). We also found a somatic mutation in BRIT1, which occurred in the splicing donor site of intro 10 in the BRIT1 gene, leading to a truncated protein. Functional analysis showed that this mutation can cause failure of foci formation of BRIT1 under irradiation. Importantly, given that BRIT1-deficient cells exhibited defective DNA repair described above, our in vitro studies showed that the BRIT1-deficient HCC cells are more sensitive to olaparib, the inhibitor of poly (ADP-ribose) polymerase (PARPi), compared to the BRIT1-proficient cells. Furthermore, we also test the inhibitory effect of olaparib in the xenograft mouse model, and found that PARPi can significantly suppress tumor growth of HCC xenografts. Collectively, our results clearly demonstrate that BRIT1 is mutated and aberrantly expressed in HCC, and targeting BRIT1 deficiency by PARP inhibitors in combination with other anti-cancer agents may provide novel and effective targeted therapies to treat BRIT1-deficient HCC.
Kaiyi Li has studied cancer molecular biology and cancer targeted therapeutics for 15+ years, and she has extensive experience in tumor mouse models, knockout mouse models to study DNA repair genes and targeted cancer therapies for breast and liver cancer. She has published more than 30 peer-reviewed papers in these research areas. Li has served on the editorial boards for the Global Journal of Surgery , and World Journal of Biological Chemistry . She has also served on numerous review committees for different funding agencies nationally and internationally.