BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin

Area of Science:

• Molecular Biology
• Cancer Genetics
• Pharmacogenomics

Background:

• Homologous recombination (HR) deficiency in cancer cells leads to synthetic lethality with PARP inhibitors.
• Previous methods struggled to precisely quantify HR activity for certain BRCA1 variants.
• The Assay of Site-Specific HR Activity (ASHRA) was developed to assess HR function.

Purpose of the Study:

• To evaluate the HR activity of 30 BRCA1 missense variants using ASHRA.
• To correlate ASHRA-measured HR activity with sensitivity to the PARP inhibitor olaparib.
• To investigate the role of activating transcription factor 1 (ATF1) in mediating resistance to PARP inhibitors.

Main Methods:

• Utilized ASHRA to measure HR activity in cells with various BRCA1 variants.
• Correlated HR activity with cellular sensitivity to olaparib.
• Assessed the impact of ATF1 expression levels on drug resistance in HR-deficient cells, including BRCA1, BRCA2, and RAD51 knockdown models.

Main Results:

• ASHRA identified intermediate HR activity in several BRCA1 variants previously difficult to classify.
• ASHRA-measured HR activity strongly correlated with olaparib sensitivity.
• The BRCA1-C61G variant, despite being HR-deficient, conferred resistance to olaparib when ATF1 expression was high, through ATF1-mediated transcriptional activation.
• High ATF1 expression conferred resistance to olaparib and cisplatin in BRCA2- or RAD51-knockdown cells, but not in BRCA1-knockdown cells.

Conclusions:

• ASHRA is a valuable tool for assessing HR activity and predicting PARP inhibitor response.
• ATF1 expression levels may serve as a predictive biomarker for PARP inhibitor and platinum agent efficacy in HR-deficient tumors, particularly those with BRCA1-C61G or alterations in other HR factors.