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

Xiangdong Lv1,2,3, Xuan Lu1,2,3, Jin Cao1,2,3

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Science (New York, N.Y.)
|September 7, 2023
PubMed

Insights

Tumor cells develop resistance to KRAS inhibitors by reprogramming proteostasis. Reactivation of inositol-requiring enzyme 1α (IRE1α) restores protein balance, driving resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Targeting mutant KRAS is crucial for cancer therapy, but tumor resistance limits efficacy.
  • KRAS inhibitors (KRASi) can induce proteostasis disturbances by down-regulating heat shock and unfolded protein responses.
  • Understanding resistance mechanisms is vital for improving cancer treatment outcomes.

Purpose of the Study:

  • To investigate the role of proteostasis reprogramming in acquired resistance to KRAS inhibitors.
  • To identify the specific molecular pathways involved in KRAS inhibitor resistance.
  • To explore potential therapeutic strategies targeting resistance mechanisms.

Main Methods:

  • Analysis of proteostasis pathways in KRAS inhibitor-resistant tumor models.
  • Investigating the regulation of inositol-requiring enzyme 1α (IRE1α) stability and activity.
  • Utilizing kinase inhibitors to modulate signaling pathways like ERK and AKT.
  • Assessing the impact of IRE1α suppression on tumor response to KRAS inhibitors.

Main Results:

  • Acquired resistance to KRAS inhibitors involves selective, ER stress-independent reactivation of IRE1α.
  • Oncogenic KRAS normally stabilizes IRE1α via ERK-dependent phosphorylation, dissociating it from the HRD1 E3-ligase.
  • In resistant tumors, reactivated ERK and hyperactivated AKT maintain IRE1α phosphorylation and stability.
  • Suppression of IRE1α effectively overcomes resistance to KRAS inhibitors.

Conclusions:

  • Proteostasis reprogramming, driven by IRE1α reactivation, is a key mechanism of KRAS inhibitor resistance.
  • The ERK and AKT signaling pathways are critical for maintaining IRE1α stability in resistant tumors.
  • Targeting IRE1α presents a promising therapeutic strategy to overcome KRAS inhibitor resistance in cancer.

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