Testing and repurposing various anticancer drugs on tumors they were not specifically designed for has often led to unexpected and positive results. So goes the story with a new study from investigators at Thomas Jefferson University’s Sidney Kimmel Cancer Center (SKCC) where researchers found that use of the metastatic breast cancer drug abemaciclib was effective at reducing cell grow in pancreatic ductal adenocarcinomas (PDAC). Findings from the new study were published recently in Molecular Cancer Research through an article titled “Abemaciclib is effective against pancreatic cancer cells and synergizes with HuR and YAP1 inhibition.”
Pancreatic cancer is one of the deadliest cancers, with patients surviving on average less than a year once the disease has spread and there is an urgent need to evaluate more therapeutic targets. “We didn’t know how abemaciclib would work in pancreatic cancer and how its effects might be improved by combining it with other drugs,” explained senior study author Jonathan Brody, PhD, professor and director of research in the department of surgery at Thomas Jefferson University, co-leader of the Gastrointestinal Cancer Program at SKCC.
To study how the drug works, the researchers assessed the effects of abemaciclib in cell lines derived from pancreatic ductal adenocarcinoma. They found that the drug caused cell death and stopped cell growth. These effects translated into decreased tumor growth in mice that received the drug compared to those that received control saline injections. Abemaciclib targets enzymes that regulate cell division. However, these enzymes only work if they are paired with another group of enzymes.
“We proposed that targeting both groups of enzymes by pairing abemaciclib with another drug might yield synergistic anticancer effects,” remarked co-lead study investigator Christopher Schultz, a doctoral candidate at Thomas Jefferson University.
The current standard of care for pancreatic care often uses several chemotherapeutics in combination with each other. The team screened for possible therapeutic candidates to use in tandem with abemaciclib and found that inhibitors of two proteins called HuR and YAP1, showed synergistic inhibition of cancer growth. They confirmed this by treating cells with either abemaciclib alone or abemaciclib plus other potential anticancer agents, an HuR or YAP1 inhibitor, and found that the combination treatment was 2–4 times more effective at inhibiting cell viability.
“Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared to no treatment (p<0.0001) accompanying a decrease in both pRb and Ki67,” the authors wrote. “We determined that inhibitors of HuR (ELAVL1), a pro-survival mRNA stability factor that regulates cyclin D1; and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional co-activator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. Additionally, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRISP-Cas9 technology.”
A significant problem in treating cancer is drug resistance, meaning cancer cells become less sensitive to chemotherapeutics after long-term exposure. The researchers treated cell lines with abemaciclib for 10–12 months, mimicking chronic therapy, at which point the cells were four times more resistant to abemaciclib. When the cells were then exposed to common therapeutic agents like gemcitabine, they did not respond to the therapy. However, the abemaciclib-resistant cells were still sensitive to HuR or YAP1 inhibitors.
These findings provide further characterization of abemaciclib and inform future clinical trials to evaluate this drug in patients. Moreover, the study is the first to show the synergy between abemaciclib and HuR/Yap1 inhibitors in vitro. Further research of this combination therapy in vivo is underway.
“There are HuR and YAP1 inhibitors that have been shown to work in vivo, but they’re not clinically available yet,” Brody concluded. “We are working on developing a HuR inhibitor that will hopefully be used for clinical trials at Jefferson.”