BRCA2 and Resistance To Therapy

This was previously released in February. I found it while doing some research. This may explain why my mom didn’t respond well to chemotherapy treatments. Cisplatin was one of the chemo drugs mom was given. Looks like BRCA2 mutations, can mutate again to resist certain chemo. This is very very scary...

Taken from HUM-MOLGEN News

Scientists have gained new insight into how changes in BRCA2 can affect a cancer's resistance to therapy. BRCA2 mutations are associated with an increase in breast and ovarian cancer risk, as the gene's normal function is to repair damaged DNA. But these cancer-causing faults are bad news for the tumour itself, as they also render it sensitive to DNA-damaging chemotherapy drugs like cisplatin. Unfortunately, many BRCA2 tumours develop resistance to cisplatin.

Two papers published online in Nature reveal how this resistance occurs. The teams, led by Alan Ashworth and Toshiyasu Taniguchi, show that some cancer cells can acquire secondary 'reactivating' mutations in their BRCA2 gene, switching it back on and allowing the cancer to repair the DNA damaged by the drug's assault. Such mutations were found in several cisplatin-resistant ovarian cancer patients. The discovery raises the possibility that blocking BRCA2 function in such patients might allow doctors to overcome drug resistance and continue with cisplatin treatment.

Authors:
Alan Ashworth (The Institute of Cancer Research, London, UK)

Toshiyasu Taniguchi (Fred Hutchinson Cancer Research Center, Seattle, WA, USA)

Abstract from Author, Toshiyasu Taniguchi's Paper:

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1, led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.