Study Indicates Some Cancer Treatments Increase the Abundance of a Protein Known to Cause Tumor Mutations

December 19, 2023 by Katelyn Queen, PhD

Steve Roberts, Ph.D.

Thirty percent of all human tumor samples have mutations caused by several enzymes called Apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases. These mutations have been shown to lead to tumor formation and progression while also contributing to relapse and therapeutic resistance. Of these enzymes, APOBEC3A (A3A) is a major contributor to APOBEC-induced mutations. However, how A3A is regulated in cancer cells and influenced by therapeutics, such as proteosome inhibitors, is still unclear.

New work from the lab of University of Vermont Cancer Center member Steve Roberts, Ph.D., and colleagues, finds that drugs used to treat certain types of cancers can have the unintended consequence of increasing the abundance of proteins, such as A3A, that may lead to faster tumor progression or therapeutic resistance. One of these drug classes is proteosome inhibitors, which are currently used to treat multiple myeloma. This work highlights how considering increased A3A abundance in patients treated with proteosome inhibitors is an important factor for understanding patient responses. 

Future work will focus on understanding how elevated A3A in patients receiving proteosome inhibitor treatment influences tumor progression and relapse. Based on these findings, the lab will investigate new targets to enhance patient outcomes. 

This work was championed by graduate students Margo Coxon and Madeline Dennis, with contributions from the lab of John Maciejowski, Ph.D., at the Sloan Kettering Institute, and Alan Goodman, Ph.D., and Sascha Duttke, Ph.D., at Washington State University. 

Read the article in NAR Cancer here.