Abstract A092: DNA repair proficiency predicts disparities in triple negative breast cancer outcomes

Abstract

Abstract Breast cancer remains as one of the most lethal type of gynecological cancers in women. Among various subtypes, triple negative breast cancer (TNBC) is the most aggressive and difficult to treat subtype due to limited therapeutic options. African American women have higher death rate from breast cancer than women of other racial and ethnic groups. Additionally, the incidence of germline BRCA1 mutations is much lower among African American women diagnosed with TNBC, than the women of the other races or ethnicities. Mechanistically, increased DNA repair and cell cycle checkpoint activation remain as the foremost reasons behind TNBC tumor resistance to chemotherapy and recurrence. We used a CHK1 inhibitor prexasertib to inhibit cell cycle checkpoint activation in TNBC cells. Interestingly, we found that prexasertib treatment promotes both proteasome-mediated degradation of BRCA1 and RAD51 proteins and affects their transcript levels. Analysis of DNA repair efficiency in prexasertib treated TNBC cells revealed reduction in homologous recombination efficiency compared to control cells. Based on these results, we hypothesized that prexasertib treatment induced homologous recombination deficiency (HRD) should cause synergistic lethality when combined with PARP inhibitors (PARPi) in TNBC cells. As predicted, combined treatment of TNBC cells with prexasertib and PARPi olaparib resulted in increased DNA strand breaks, gH2AX foci and nuclear disintegration, an indicator of mitotic catastrophe. Similarly, these drug combinations also caused synergistic lethality in multiple TNBC cell lines when compared to single drug-treatments, as indicated by combination index (CI) values. Since RAD51 is the downstream effector repair protein in FA-BRCA pathway-mediated HR, we evaluated TCGA data for RAD51 gene expression using UALCAN portal. Computational analysis revealed that RAD51 overexpression in breast tumors compared to normal breast tissues, in particular, TNBC subtype showed highest RAD51 expression compared to other subtypes of breast cancer. Overall, these data show RAD51 as a poor prognostic marker for breast cancer patients. Interestingly, there was a discrepancy in RAD51 expression levels in distinct racial groups, where African American and Asian breast cancer patients showed high RAD51 expression compared to Caucasian breast cancer patients. Consistent with these observations, African American and Asian TNBC patients show decreased survival probability. Based on these data, RAD51 could be a biomarker for aggressive TNBC and racial disparity in breast cancer therapeutic outcomes. As positive correlation exists between RAD51 and CHEK1 expression in breast cancer, in-vitro preclinical data presented here provides additional mechanistic insights for further evaluation of the rational combination of prexasertib and olaparib for improved prognosis and to reduce racial disparity in TNBC. Citation Format: Chinnadurai Mani, Jonnalagadda Shirisha, Awasthi Sanjay, Manne Upender, Palle Komaraiah. DNA repair proficiency predicts disparities in triple negative breast cancer outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A092.