Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocar-cinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profi ling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fi ne-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregula-tion and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopuri-fi ed lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition.SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregu-lation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency.

Automated summary

The mechanisms of metabolic adaptation of pancreatic ductal adenocarcinoma cells to pharmacologic inhibition of RAS-MAPK signaling are not well understood. This study reveals that the MEK inhibitor trametinib leads to downregulation of c-MYC and increased MiT/TFE-dependent lysosome biogenesis in PDA cells. Furthermore, it is found that increased ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Inhibition of iron utilization sensitizes PDA cells to MEKi.