Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer

Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

Automated summary

This study found that mutations in K-Ras in pancreatic adenocarcinomas (PDAC) can stimulate the ERK pathway and activate high levels of ERK, leading to cell senescence. However, advanced PDAC lesions show lower levels of ERK activation. Restoring ERK hyperactivation in PDAC can induce cell growth arrest and expression of senescence markers. ERK-dependent senescence in PDAC is characterized by a nucleolar stress response, including selective depletion of nucleolar phosphoproteins and the formation of intranucleolar foci containing RNA polymerase I. Combining ribosome biogenesis inhibitors with ERK hyperactivation can enhance the senescence response in PDAC cells.