Although chemotherapy is the standard treatment for pediatric acute lymphoblastic leukemia (ALL), and has made it one of the most survivable forms of childhood cancer, thiopurines of the chemotherapy drug class can cause mutations that result in relapse. The findings were published in Nature Cancer.
Previously, it was unknown whether acquired drug-resistant mutations in ALL are present at diagnosis or induced by treatment. The current findings are the first evidence in pediatric cancer that mutations can be caused by chemotherapy.
“The findings provide a paradigm shift in understanding how drug resistance evolves,” Jinghui Zhang, PhD, Division of Computational Biology at St. Jude Children’s Research Hospital, said in a statement. “The results also suggest potential treatment strategies for ALL patients who relapse, including screening, to identify those who should avoid additional thiopurine treatment.”
The study used samples from pediatric patients with ALL who had relapsed in the United States, China and Germany. More than 1000 samples were collected from different time points in the treatment. Samples from 181 patients were collected at diagnosis, remission, and relapse.
The authors identified a mutational signature, which reflects the history of genetic changes in a cell, to decipher the process. Thiopurine-induced mutations were linked to genes that are mutated in leukemia and render ALL resistant to thiopurines through mismatch repair.
A mutation in the tumor suppressor gene TP53 promoted resistance to multiple chemotherapy drugs, relapse during treatment, and poor response to treatment. The researchers were able to replicate the thiopurine-induced TP53 mutations and chemotherapy resistance. They noted that this can be reversed by pharmacological p53 reactivation.
They estimate that treatment-induced mutations play a role in 25% of pediatric ALL recurrence. In the study, 8% of patients had signs of thiopurine-associated mismatch repair.
“This study not only changes our ALL treatment considerations, but also opens the door to mechanistically study how defective repair generates drug-resistant mutations,” said Bin-Bing Zhou, PhD, of Shanghai Children’s Medical Center.
Despite the findings, the benefits of the thiopurine class continue to outweigh its risks, with most patients unaffected by the thiopurine-induced mutations, the researchers noted.
“In the future, it may be possible to monitor the bone marrow during treatment as a way to detect these mutational signatures early enough to help identify at-risk patients who may be candidates for emerging therapies such as CAR T cells,” Zhang said.
The first findings were originally presented at the American Association for Cancer Research’s annual meeting in 2021.
Yang F, Brady SW, Tang C, et al. Chemotherapy and mismatch repair deficiency interact to fuel TP53 mutagenesis and ALL relapse. Wet Cancer. Published online July 22, 2021. doi:10.1038/s43018-021-00230-8