FGFR2 recognized as key driver in KRAS-mutated pancreatic most cancers development

Backside line: Precancerous pancreatic lesions and a few pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations had higher-than-normal expression of the FGFR2 protein, and FGFR2 inactivation delayed KRAS-mutated PDAC improvement in mice.

Journal by which the examine was revealed: Most cancers Analysis, a journal of the American Affiliation for Most cancers Analysis

Writer: Claudia Tonelli, PhD, a analysis investigator within the laboratory of AACR Previous President David A. Tuveson, MD, PhD, FAACR, at Chilly Spring Harbor Laboratory

Background: PDAC is the commonest kind of pancreatic most cancers, a extremely deadly malignancy that’s usually preceded by precancerous lesions. These lesions are comparatively frequent, however solely a small portion will progress to PDAC, Tonelli defined.

Whereas mutations within the KRAS protein are recognized to drive pancreatic most cancers, these don’t seem like ample to advertise the transition from precancerous lesions to most cancers, Tonelli famous. “Understanding the extra pathways that promote development from a precancerous pancreatic lesion to a malignant tumor might assist determine extra viable remedy methods in addition to most cancers interception approaches to cease PDAC from creating within the first place,” she added.

How the examine was performed: By analyzing murine and human pancreatic tissue specimens, Tonelli and colleagues discovered that, in contrast with regular tissue, FGFR2 expression was increased in KRAS-mutated precancerous lesions and a few KRAS-mutated PDAC. Notably, FGFR2 expression in murine precancerous lesions correlated with a rise in mutant KRAS signaling.

“We all know that precancerous pancreatic lesions usually carry KRAS mutations,” stated Tonelli. “Our remark that FGFR2 expression was related to elevated KRAS signaling means that FGFR2 might play a key position in driving the development of KRAS-mutated precancerous lesions to malignancy.”

Outcomes: In keeping with this speculation, the researchers discovered considerably fewer precancerous lesions and delayed PDAC tumors formation in KRAS-mutated mice by which the FGFR2 gene had been deleted in contrast with these with an intact FGFR2 gene. As well as, the mixed inhibition of FGFR2 and one other signaling protein, EGFR, considerably decreased the formation of precancerous lesions in mice carrying mutated KRAS.

Writer’s feedback: In line with Tonelli, the findings counsel that focusing on FGFR2 might probably profit sufferers at excessive danger of their precancerous lesions progressing to PDAC. Whereas FGFR inhibitors are clinically obtainable, Tonelli cautioned that their effectiveness in intercepting PDAC would first should be examined in medical trials earlier than they could possibly be used for this function.

“Our examine offers vital insights into pancreatic most cancers improvement and will information the event of methods for the interception and prevention of pancreatic malignancies,” she summarized.

Examine limitations: A limitation of the examine is that it didn’t straight study whether or not FGFR2 inactivation in precancerous lesions would additionally block or delay subsequent PDAC. This could possibly be addressed in future research by performing long-term FGFR2 inhibition, or alternatively by genetic experiments, Tonelli famous.