Mechanism of Cisplatin-Resistance in BRCA2-Related Ovarian Cancers

Our increasing molecular knowledge of the pathways involved in cancer development continues to suggest potential avenues for molecularly-targeted cancer therapies.  However, aside from a few examples (Gleevec, Herceptin, and others), molecularly-targeted therapy is still not a reality for most cancer types.

Individuals born with mutations in the BRCA2 gene have a substantially elevated lifetime risk for breast cancer, ovarian cancer, and several other cancers.  Recent work has shown that loss of BRCA2 function results in defects in a DNA repair process called "homologous recombination."  Evidence has emerged that PARP-inhibitor drugs, which are currently under development as possible treatments for BRCA2-associated cancers, are potent killers in vitro of cells lacking BRCA2.  In fact, the loss of homologous recombination capacity in BRCA2 mutant cells is thought to be an achilles heel that may be exploited both by PARP-inhibitors and also by platinum compounds such as cisplatin (BRCA2-mutated ovarian cancers seem to be particularly sensitive to cisplatin). 

However, individuals treated with another molecularly-targeted therapy, Gleevec, for chronic myelogenous leukemia have developed resistance to the drug in some cases.  Indeed, individuals with BRCA2-related ovarian cancers ultimately develop cisplatin resistance. 

Two papers published online today in the journal Nature (abstracts available here and here) show us why this is the case at least in a subset of cases in individuals with BRCA2 mutations.  Basically, various revertent mutations can occur under selection of cisplatin or PARP-inhibitors that result in expression of a functional BRCA2 protein again that improves the cellular capacity to promote homologous recombination, thus eliminating the achilles heel.  Thus, BRCA2 loss is involved in the establishment of the cancer, but is not necessary for its maintenance (especially under the selective pressure of treatment with Cisplatin).

This has a number of implications:

• Genotyping of tumors in individuals with BRCA2 mutations may help to predict whether PARP-inhibitors or platinum-containing compounds are likely to be effective in their treatment
• BRCA2-associated tumors that have acquired PARP/cisplatin-resistance may be treatable with a combination of cisplatin or a PARP-inhibitor plus a secondary drug disrupting homologous recombination
• Although PARP-inhibitors have not yet reached the clinic, we now know of one potential challenge in their potential use
• As some sporadic ovarian cancers seem to have lost BRCA2 function, these findings may be relevant to understanding treatment resistance even in some ovarian cancers that apparently are not hereditary