A study in the Proceedings of the National Academy of Sciences (GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant-driven pancreatic tumorigenesis in mice) shows that inhibiting a specific protein may be a way to combat the deadly pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC), which accounts for 95% of all cases of pancreatic cancer, remains an aggressive type of malignant tumor in need of more effective therapies. The five-year survival rate is only about 5%, though surgery offers the only opportunity for a cure. In the United States alone, PDAC killed 39,590 people in 2014.
Mutations in the KRAS oncogene are present in 90% of PDACs. Previous studies have shown that KRAS mutations drive pancreatic tumorigenesis and is required for tumor maintenance, suggesting KRAS as a promising therapeutic target. However, the effect of drugs directly targeting KRAS turned out to be disappointing, highlighting the need to identify new therapeutic targets.
PDAC is very difficult to treat due to its excessive local invasion and early systemic dissemination. The glucose-regulated protein (GRP) is over-expressed in a variety of cancers including pancreatic cancer and associated with invasion and metastasis. Elevated GRP78 expression promotes the proliferation, migration, and invasion of pancreatic cancer cells and may predict poor prognosis in PDAC.
The new study describes an approach to stop the development of pancreatic cancer. In the work, the researchers demonstrated in a genetically engineered mouse model that expressing only 50% of the amount of GRP78 (a mechanism called haploinsufficiency ) stopped KRAS-driven pancreatic tumorigenesis. Further investigation showed that GRP78 haploinsufficiency in the pancreata led to reduction of epidermal growth factor receptor (EGFR), a protein that plays essential roles in both normal physiological conditions and cancerous conditions.
The researchers drew the conclusion that GRP78 is involved in PDAC development. Pharmacological inhibition of GRP78 could be a promising approach to improve the management of PDAC. (Cusabio offers Recombinant FGFR1, KRAS, GRP78, and EGFR proteins.)
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