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Rewired proteostasis in KRAS inhibitor resistance

  1. Alex Eccleston
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Small molecule inhibitors that target G12C oncogenic mutants of the KRAS GTPase are approved for the treatment of non-small cell lung cancer (NSCLC), but drug resistance can ensue. Writing in Science, Lv et al. report that oncogenic KRAS ensures protein quality control in cancer cells by stabilizing the major mediator of the unfolded protein response (UPR), IRE1α. Cells resistant to the approved KRAS-G12C inhibitor sotorasib are dependent on IRE1α, and an IRE1α inhibitor overcomes sotorasib resistance in mouse models.

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Nature Reviews Drug Discovery 22, 871 (2023)

doi: https://doi.org/10.1038/d41573-023-00155-0

References

  1. Lv, X. et al. Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors. Science 381, eabn4180 (2023)

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