Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol β) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechanistically, P242R Pol beta acts as a translesion polymerase and prefers to insert the correct nucleotide opposite cisplatin intrastrand crosslinks leading to the activation of the nucleotide excision repair (NER) pathway, removal of crosslinks, and resistance to cisplatin. In contrast, wildtype (WT) Pol beta preferentially inserts the incorrect nucleotide initiating mismatch repair and cell death. Importantly, in a mouse xenograft model, tumors derived from lung cancer cells expressing WT Pol Beta displayed a slower rate of growth when treated with cisplatin, whereas tumors expressing P242R Pol Beta had no response to cisplatin. Pol beta is critical for mediating crosstalk in response to cisplatin and the current data strongly suggests that the status of Pol Beta influences cellular responses to crosslinking agents, and that Pol beta is a promising biomarker to predict responses to specific chemotherapies. Finally, these results highlight that the genetic status of the germline is a critical factor in the response to cancer treatment. Implications: Pol beta has prognostic biomarker potential in the treatment of cancer with cisplatin and perhaps other intrastrand crosslinking agents.
- Received July 5, 2016.
- Revision received December 16, 2016.
- Accepted December 21, 2016.
- Copyright ©2017, American Association for Cancer Research.