Seeking to understand the factors associated with PARP inhibitor resistance and improve outcomes for breast cancer patients.

Impact

In normal cells, DNA damage is recognized and repaired so that they can continue to grow. However, in breast cancer cells with inherited mutations in genes such as BRCA1 or BRCA2, the ability to repair damaged DNA is impaired. This vulnerability in cancer cells has been exploited with treatments, such as PARP inhibitors which block alternative DNA repair processes these tumor cells depend on. Although these drugs are effective in BRCA-mutated tumors, tumor cells can further mutate to restore BRCA function and overcome the lethal effect of the therapy.  Dr. Tutt and his team are studying this phenomenon and hope to define steps that can block it and reduce PARP inhibitor resistance and to design new ways to treat these drug resistant breast cancers.

What’s Next

They are taking two approaches to address the problem of PARP resistance. In laboratory studies, the team has found that reverse mutations from the reactivated gene result in the production of a protein that is different from the normal protein. Moreover, the differences can be detected by the immune system as a foreign substance. Therefore, one approach will be to confirm these findings in the clinic by testing patient blood samples for evidence of an immune response against the tumor. The second line of research will involve isolating tumor cells from patients that develop PARP inhibitor resistance and grow them in the laboratory to study them in detail. Through these two lines of investigation, they hope to define methods to release the brakes on the immune system so that PARP resistance can be prevented or develop novel strategies to treat drug resistant tumors.