Most patients with metastatic urothelial cancer will become resistant to therapy. New research published in Nature Genetics showed that chemotherapy also shapes the genetic evolution of remaining urothelial cancer cells clone to become drug-resistant.
Researchers from Weill Cornell Medical Center (New York, NY) and the University of Trento (Trento, Italy) found that urothelial cancer cells mutate following chemotherapy treatment, and these mutations provide these tumor cells with an evolutionary advantage to survive chemotherapy.
For the study, researchers collected and analyzed the DNA using whole-exome sequencing of 72 tumor samples from 32 patients with various stages of disease. Of those, 28 had developed metastatic urothelial cancer at the time of enrollment or at a later point during the study; two patients consented to rapid autopsies, conducted within 6 hours after death, enabling researchers to collect samples of tumors from different body sites that capture the natural history of the tumors’ evolution.
The findings showed that the primary untreated and advanced chemotherapy-resistant tumors did not share the majority of mutations. Instead, as the tumor spread, it branched out and grew new mutations that were opposite from those in the primary tumor. The mutations appeared to happen early in the diseases’ development.
Additionally, the researchers found that two molecular pathways—the integrin signaling and the L1-cell adhesion molecule signaling pathways—particularly accumulated higher levels of mutations after chemotherapy. The researchers also studied the mechanisms underlying the mutational changes they observed in chemotherapy-resistant urothelial cancer. They found that chemotherapy-treated urothelial cancers have more mutations caused by a family of proteins called APOBECs, that mutate single-stranded DNA.
“By understanding how these urothelial cancer clones evolve at the genetic level over time and through different selective pressures such as treatment, we are hoping to translate our findings to strategies that reverse or prevent the emergence of chemotherapy resistance in bladder cancer patients.” said lead study author Bishoy M Faltas, MD, in a statement.
