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  3. Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth

  • Nat Cell Biol. 2023 Jan 12. doi: 10.1038/s41556-022-01049-w.
Rui Tang # 1,  Emily G Shuldiner # 2,  Marcus Kelly 3 4,  Christopher W Murray 3,  Jess D Hebert 1,  Laura Andrejka 1,  Min K Tsai 1 3,  Nicholas W Hughes 1,  Mitchell I Parker 5 6,  Hongchen Cai 1,  Yao-Cheng Li 7,  Geoffrey M Wahl 7,  Roland L Dunbrack 5,  Peter K Jackson 3 4,  Dmitri A Petrov 2 3 8,  Monte M Winslow 9 10 11
Affiliations

Affiliations

  • 1 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Biology, Stanford University, Stanford, CA, USA.
  • 3 Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Baxter Laboratories, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Molecular Therapeutics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 6 Molecular and Cell Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, PA, USA.
  • 7 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  • 8 The Chan Zuckerberg BioHub, San Francisco, CA, USA.
  • 9 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu.
  • 10 Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu.
  • 11 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu.
  • # Contributed equally.
PMID: 36635501 DOI: 10.1038/s41556-022-01049-w
Abstract

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung Cancer remains difficult to treat, and our understanding of the regulators of Ras signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung Cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode Sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung Cancer models, we show that HRAS and NRAS are suppressors of KRASG12D-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung Cancer cell lines. Mechanistically, Ras paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung Cancer models, we confirm that Ras paralogues are specific suppressors of KRAS-driven lung Cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven Cancer in a multiplexed manner in vivo and highlights the role Ras paralogue imbalance in oncogenic KRAS-driven lung Cancer.

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