Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells
The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]^(2+) (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR-deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.
© 2017 National Academy of Sciences. Contributed by Jacqueline K. Barton, May 25, 2017 (sent for review April 24, 2017; reviewed by Dale L. Boger and Dong Wang). Published online before print June 20, 2017. We thank Ilan (Lanny) Kirsch for helpful discussions. We thank Wesley Chang, Jay Danao, and Brendon Frank for advice and assistance with imaging studies. Kelsey Boyle, Adam Boynton, and Adela Nano provided constructive comments on the manuscript. We also thank the NIH (Grant GM33309), Amgen, and the Moore Foundation for support (to J.K.B.). Author contributions: J.M.B., A.G.W., and J.K.B. designed research; J.M.B., A.G.W., and N.F.M. performed research; J.M.B., A.G.W., N.F.M., and J.K.B. analyzed data; and J.M.B., A.G.W., and J.K.B. wrote the paper. Reviewers: D.L.B., The Scripps Research Institute; and D.W., University of California, San Diego. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1706665114/-/DCSupplemental.
Published - PNAS-2017-Bailis-6948-53.pdf
Supplemental Material - pnas.201706665SI.pdf