Abstract
PM01183 is a novel marine-derived covalent DNA binder in clinical development. PM01183 is structurally similar to trabectedin (yondelis, ecteinascidin-743) except for the C subunit, and this modification is accompanied by different pharmacokinetics in cancer patients. We here characterize the interaction of PM01183 with the nucleotide excision repair (NER) pathway in comparison with trabectedin. Our results show for the first time that although neither PM01183 nor trabectedin is repaired by NER, both compounds are able to interfere with the NER machinery thereby attenuating the repair of specific NER substrates. We further show that the NER activity is increased in 3 of 4 cellular models with acquired resistance to cisplatin or oxaliplatin, confirming the involvement of NER in the resistance to platinum derivatives. Importantly, both PM01183 and trabectedin show unchanged or even enhanced activity toward all 4 cisplatin- and oxaliplatin-resistant cell lines. We finally show that combinations of PM01183 and cisplatin were mostly synergistic toward both parental and cisplatin-resistant ovarian carcinoma cells as indicated by Chou and Talalay analysis. These data show that the C subunit of trabectedin can be subjected to at least some structural modifications without loss of activity or NER interaction. While PM01183 and trabectedin appear functionally similar in cellular models, it is likely that the differences in pharmacokinetics may allow different dosing and scheduling of PM01183 in the clinic that could lead to novel and/or increased antitumor activity. Taken together, our results provide a mechanistic basis to support clinical trials of PM01183 alone or in combination with cisplatin.
Highlights
PM01183 is a novel marine-derived ecteinascidin derivative in clinical development [1]
Exposure of human fibroblasts to UV irradiation (Fig. 1B left) or to S23906, another covalent DNA minor groove binder with similar binding specificity as the ecteinascidins (31, 32; Fig. 1B right), was accompanied by a dose-dependent increase in unscheduled DNA synthesis (UDS) that was nucleotide excision repair (NER) specific because no influence on UDS was observed for the NER-deficient XPA cells
The results show that trabectedin exposure leads to the formation of biotinylated nuclear foci, which persists throughout the 4-hour wash-out period (Fig. 2A)
Summary
PM01183 is a novel marine-derived ecteinascidin derivative in clinical development [1] Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Trabectedin has an unusual interaction with the nucleotide excision repair (NER) machinery, which distinguishes it from other covalent DNA binders. One study indicated that the C subunit was essential for interaction with NER proteins [3], whereas another study reported that the C subunit had no influence [4]
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