HMGA 2 as a functional antagonist of PARP 1 inhibitors in tumor cells

Poly(ADP‐ribose) polymerase 1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP 1 inhibitors. Expression of HMGA 2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA 2 and PARP 1 in DNA damage‐induced PARP 1 activity. We used human triple‐negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA 2 colocalizes and interacts with PARP 1. High cellular HMGA 2 levels correlated with increased DNA damage‐induced PARP 1 activity, which was dependent on functional DNA ‐binding AT ‐hook domains of HMGA 2. HMGA 2 inhibited PARP 1 trapping to DNA and counteracted the cytotoxic effect of PARP inhibitors. Consequently, HMGA 2 decreased caspase 3/7 induction and increased cell survival upon treatment with the alkylating methyl methanesulfonate alone or in combination with the PARP inhibitor AZD 2281 (olaparib). HMGA 2 increased mitochondrial oxygen consumption rate and spare respiratory capacity and increased NAMPT levels, suggesting metabolic support for enhanced PARP 1 activity upon DNA damage. Our data showed that expression of HMGA 2 in cancer cells reduces sensitivity to PARP inhibitors and suggests that targeting HMGA 2 in combination with PARP inhibition may be a promising new therapeutic approach.