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

  • Cancer Discov. 2022 Sep 2;12(9):2198-2219. doi: 10.1158/2159-8290.CD-22-0044.
Mirunalini Ravichandran  1  2 ,  Jingjie Hu  1  2 ,  Charles Cai  3 ,  Nathan P Ward  4 ,  Anthony Venida  1  2 ,  Callum Foakes  1  2 ,  Miljan Kuljanin  5 ,  Annan Yang  6 ,  Connor J Hennessey  6 ,  Yang Yang  1  2 ,  Brandon R Desousa  7  8 ,  Gilles Rademaker  1  2 ,  Annelot A L Staes  1  2 ,  Zeynep Cakir  1  2 ,  Isha H Jain  7  8 ,  Andrew J Aguirre  6  9 ,  Joseph D Mancias  5 ,  Yin Shen  3 ,  Gina M DeNicola  4 ,  Rushika M Perera  1  2  10
Affiliations
  • 1. Department of Anatomy, University of California, San Francisco, San Francisco, California.
  • 2. Department of Pathology, University of California, San Francisco, San Francisco, California.
  • 3. Department of Neurology, Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
  • 4. Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida.
  • 5. Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 7. Department of Biochemistry, University of California, San Francisco, San Francisco, California.
  • 8. Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, California.
  • 9. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 10. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
PMID: 35771494 DOI: 10.1158/2159-8290.CD-22-0044
Abstract

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling 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 fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-Myc downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified 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 upregulation 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. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    Sotorasib
    99.70%, KRAS G12C Inhibitor
    target: Ras
    Research Areas: Cancer