RNA Splice Variants May Be New Therapeutic Targets for African American Men with Prostate Cancer

RNA splicing variants were found to be critical drivers of prostate cancer aggressiveness and therapeutic resistance in African American men.

RNA splice variants may have the potential to serve as novel biomarkers and molecular targets for combating aggressive prostate cancer in African American men, according to researchers at the George Washington University (GW) Cancer Center. They report in Nature Communications that the genetic basis for prostate cancer disparities among African American men and Caucasian men may be partially explained by differential RNA splicing.

“Differences in the aggressiveness of prostate cancer, as well as other types of cancers, along racial and ethnic lines is dictated by myriad biological factors, including gene mutations and polymorphisms, epigenetic events, and possibly post-translational modification,” said principle study investigator Norman Lee, PhD, who is a professor of pharmacology and physiology at the GW School of Medicine and Health Sciences.

It is well documented that African American men have a higher incidence of prostate cancer and a worse prognosis compared with men of European American decent. Now, it turns out there may be a way to identify some of the molecular mechanisms behind this disparity and develop targeted therapies specifically for African American men with prostate cancer.

Lee and his team report that the RNA splicing landscape of prostate cancer among different ethnic groups has not been fully examined. In this current investigation, the researchers identified novel genome-wide, race-specific RNA splicing events. They were able to link specific RNA splicing events as critical drivers of prostate cancer aggressiveness and therapeutic resistance in African American men.

The researchers found that African American men appear to have enriched splice variants of PIK3CD, FGFR3, TSC2, and RASGRP2, and these variants may contribute to greater oncogenic potential. They found that ectopic overexpression of a newly cloned African American–enriched variant of PIK3CD-S in European American prostate cancer cell lines enhanced AKT/mTOR signaling. This variant also increased proliferative and invasive capacity of prostate cancer in vitro and lead to resistance to the selective PI3Kd inhibitor idelalisib in mouse xenograft models.

Overall, they found the African American mRNA variants encode protein isoforms that make a tumor more aggressive, whereas the protein isoforms generated in European Americans appear to make prostate cancers less aggressive. These findings may now lead to new ways of treating other cancers as well. It is theorized that patients with non-Hodgkin lymphoma may not be responding to agents such as idelalisib because of specific mRNA variations.

“What is becoming apparent is that mRNA splicing may play a critical role in primary and acquired resistance to cancer therapies. Consequently, the sequencing of cancer genomes in order to understand cancer biology should take into account not only gene mutations, but also mRNA splicing events. By concentrating only on the former, we end up missing the latter, which represent important diagnostic markers for therapeutic resistance and cancer aggressiveness,” Dr. Lee told OncoTherapy Network.