Therapeutic approaches based on the principle of synthetic lethality are an attractive strategy for cancer treatment. Since DNA repair pathway aberrations are common in tumor cells but are largely absent in normal cells, agents that target DNA repair-deficient cells may have a clinically exploitable therapeutic window. Some chemotherapeutic agents, such as platinum-based therapy, take advantage of this principle, but their overall toxicity is still significant. PARP inhibitors, on the other hand, were developed to specifically target homologous recombination (HR) deficient cancer cells and have minimal effect on normal cells.
The remarkable success of PARP inhibitors raised the possibility that other tumor DNA repair pathway deficiencies could also be targeted using a synthetic lethal approach. Irofulven is a DNA damaging agent that creates DNA lesions that can only be repaired by the nucleotide excision repair (NER) pathway, and it was demonstrated nearly 20 years ago that irofulven preferentially kills NER deficient cells. We, therefore, decided to explore the application of irofulven to a solid tumor type with a significant proportion of NER deficient cases. At least 10% of bladder cancer cases are NER deficient due to mutations in ERCC2. We showed that introducing ERCC2 mutations into bladder cancer cell lines renders the cells sensitive to irofulven in vitro and in vivo. Importantly, when NER deficient cells were trained to become platinum-resistant, the cells remained sensitive to irofulven. These results suggest that NER deficient bladder cancer cases may still respond to irofulven treatment following progression on platinum therapy.
We also investigated whether bladder cancer cases without ERCC2 mutations also show signs of NER deficiency. We identified a composite mutational signature extracted from whole-exome sequencing data that was strongly associated with ERCC2 mutational status. Interestingly, we found that the ERCC2 mutation-associated signature was also present in another 10% of bladder cancer cases that lacked an ERCC2 mutation but were sensitive to platinum therapy, suggesting that the signature may be useful in identifying patients likely to benefit from platinum-based therapy.
In summary, our preclinical investigations suggest that up to 20% of bladder cancer cases, both with and without ERCC2 mutations, are NER deficient and sensitive to irofulven. Clinically, most NER-deficient tumors respond well to platinum treatment but appear to remain sensitive even when platinum resistance emerges. Thus, irofulven may become an important therapeutic modality in either platinum-refractory or platinum-ineligible patients. A clinical trial to validate this working hypothesis is planned at the Rigshopitalet, in Copenhagen, Denmark.
Written by: Kent W. Mouw, MD, PhD, Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital, Boston, MA & Zoltan Szallasi, MD, Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA
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