A team of researchers have used targeted CRISPR screening and have identified PRMT5 as a synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer. It remains one of the deadliest of any cancer types. Unfortunately, the disease is mostly asymptomatic until the late stages. Additionally, the current treatment strategies are relatively ineffective. Therefore, where possible, surgery remains the only curative therapy. However, only 15-20% of PDAC patients are eligible for surgery. Current chemotherapy combinations have severe side effects. As a result, novel drug combinations that can result in better therapeutic value are urgently needed.
Better understanding the significant drivers of pancreatic cancer is important to yield novel and more effective treatment strategies. Cancer genome sequencing efforts have identified several recurrent genetic alterations. These include oncogenic KRAS mutations which are observed in 93% of PDAC tumours. Others include loss-of-function mutations in CDKN2A, TP53 and SMAD4. Nonetheless, none of these genetic alterations are currently targetable.
In a study, published in PNAS, researchers used in vivo CRISPR screening to identify effective and potentially synergistic lethal drug combinations for PDAC. They specifically aimed to identify new targets whose inhibition would create conditional vulnerability with gemcitabine. In other words, which targets would synergise with gemcitabine. Gemcitabine is a first-line or second-line chemotherapy for most PDAC patients.
This approach revealed protein arginine methyltransferase gene 5 (PRMT5) as a promising druggable candidate. They found that PRMT5 inhibition created synergistic vulnerability of PDAC cells to gemcitabine. At the molecular level, the team found that this synergistic cytotoxicity with gemcitabine was due to depleted replication protein A levels and impaired non-homologous end joining DNA repair. Therefore, combinatorial treatment led to excessive DNA damage accumulation and subsequent cell death.
The team’s initial screening and subsequent validation experiments showed that PRMT5 inhibition resulted in the synergistic vulnerability of PDAC cells to gemcitabine. This novel combination creates conditional lethality through the accumulation of excessive DNA damage and cell death. These findings show the value of unbiased CRISPR genetic screenings, combined with a clinically relevant model system, in identifying synthetic lethal drug combinations.
Image credit: By jatupronv – canva.com