Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors

Science. 2023 Sep 8;381(6662):eabn4180. doi: 10.1126/science.abn4180. Epub 2023 Sep 8.


Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Drug Resistance, Neoplasm*
  • Endoribonucleases*
  • Enzyme Inhibitors* / pharmacology
  • Extracellular Signal-Regulated MAP Kinases*
  • Heat Shock Transcription Factors* / metabolism
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Protein Serine-Threonine Kinases
  • Proteostasis*
  • Proto-Oncogene Proteins p21(ras)* / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras)* / genetics


  • Endoribonucleases
  • Extracellular Signal-Regulated MAP Kinases
  • KRAS protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Enzyme Inhibitors
  • Antineoplastic Agents
  • ERN1 protein, human
  • HSF1 protein, human
  • Heat Shock Transcription Factors