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  2. Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS

Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS

  • Nat Cancer. 2023 Jun 5. doi: 10.1038/s43018-023-00575-2.
Yuta Adachi 1 Ryo Kimura 1 Kentaro Hirade 1 Shogo Yanase 1 Yuki Nishioka 1 Natsumi Kasuga 1 Rui Yamaguchi 2 3 Hiromichi Ebi 4 5
Affiliations

Affiliations

  • 1 Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
  • 2 Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
  • 3 Division of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
  • 4 Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan. hebi@aichi-cc.jp.
  • 5 Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. hebi@aichi-cc.jp.
Abstract

Tumor cells evade targeted drugs by rewiring their genetic and epigenetic networks. Here, we identified that inhibition of MAPK signaling rapidly induces an epithelial-to-mesenchymal transition program by promoting re-localization of an apical-basal polarity protein, Scribble, in oncogene-addicted lung Cancer models. Mis-localization of Scribble suppressed Hippo-YAP signaling, leading to YAP nuclear translocation. Furthermore, we discovered that a Ras superfamily protein MRAS is a direct target of YAP. Treatment with KRAS G12C inhibitors induced MRAS expression, which formed a complex with SHOC2, precipitating feedback activation of MAPK signaling. Abrogation of YAP activation or MRAS induction enhanced the efficacy of KRAS G12C inhibitor treatment in vivo. These results highlight a role for protein localization in the induction of a non-genetic mechanism of resistance to targeted therapies in lung Cancer. Furthermore, we demonstrate that induced MRAS expression is a key mechanism of adaptive resistance following KRAS G12C inhibitor treatment.

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