BRCAREV: Unravelling how reversion mutations in the BRCA1 and BRCA2 tumour suppressor genes occur

A fundamental question in cancer research is what determines the success of treatment. Currently, up to 25% of breast cancer patients (40-70% of the poor-prognosis Triple Negative subtype) and about 5% of prostate cancer patients have BRCA1/2 deficiency and are suitable for treatment with PARP inhibitors (PARPi). However, over 40% of these patients do not respond to this treatment due to resistance mechanisms, which are not fully characterised. We propose to address this question by studying how tumour cells become resistant to PARPi. In the BRCAREV project, we will combine in silico and "wet-lab" experimental approaches to dissect this problem and use the information gained in this work to generate a predictor that estimates the likelihood that a person with a particular BRCA1 or BRCA2 mutation will or will not develop resistance to PARPi. Therefore, this work will: (i) benefits patients with BRCA1/BRCA2 mutant cancers; (ii) establish some of the fundamental rules that govern how cancer-associated mutations cause drug resistance; (iii) allow both the host group (a pioneer group researching the implication of BRCA mutations in cancer) and the applicant (a highly trained researcher on cancer genomics through computational structural approaches) to combine their knowledge and to generate new one of BRCA-mutated cancer therapeutics as part of an interdisciplinary project of mutual synergistic benefit, to the researchers and patients.