“For anti-cancer drugs, even those that have been in use for a while, we don’t know how the drug resistance is caused,” said Dr. Wei Xu, professor of oncology at the University of Wisconsin Carbone Cancer Center and McArdle Laboratory for Cancer Research and senior author of the study.
“We want to identify the mechanism of drug resistance and develop biomarkers for it so that we can predict which cancer patients will benefit from certain treatments.”
Xu and her research team investigated CARM1, a protein that chemically modifies other proteins and is often overexpressed in breast and some other cancers. In the current study, they identify a new CARM1 target, a protein called MED12, and show in breast cancer cell lines that the ability of MED12 to be chemically modified by CARM1 determines if cells will be sensitive or resistant to a common breast chemotherapy treatment.
“This chemical modification of MED12 can sensitize the cells to antimetabolite drugs, including one commonly used in breast cancer, Fluorouracil (5-FU),” Xu said. “If MED12 cannot be modified by CARM1, or if MED12 is not expressed, then the cancer cells are resistant to 5-FU and survive treatment.” Charles Heidelberger, a former faculty member of McArdle Laboratory, first synthesized 5-FU in 1956.
The researchers next searched a database of breast cancers that had been excised prior to chemotherapy treatment, and while they found a handful of mutations that render MED12 completely non-functional, they did not find any mutations in MED12 that would prevent CARM1 from chemically modifying it. That information is consistent with most breast cancers being initially sensitive to 5-FU but some developing resistance during chemotherapy, possibly through 5-FU-induced genetic mutation of MED12. This research paper identifies the potential of using both the expression of MED12 and its ability to be modified by CARM1 as a biomarker before and during treatment to help physicians predict how effective a treatment might be, and when to switch course.
“If a patient will not be sensitive to a treatment, they should not be placed on that treatment. They should not be over-treated,” Xu said. “Also, we want to give timely treatments, because if you match the patient to the right treatment, you’re more likely to save someone’s life.”
Xu stressed the importance of MED12 as a biomarker, noting that while having both CARM1 and MED12 in cancer cells results in a better prognosis with chemotherapy treatment, tumors that express high levels of CARM1 are often associated with poor prognosis. Last year, her group showed that CARM1 also chemically modifies a different protein, BAF155, and that modified BAF155 results in increased metastasis.
“We want to continue identifying as many CARM1 substrates as we can so that we can keep putting these pieces of the puzzle together,” Xu said.
The study is published in Science Advances and is funded by a Department of Defense Era of Hope Award.
University of Wisconsin School of Medicine and Public Health