1. Academic Validation
  2. 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. [email protected]
  • 10 Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  • 11 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  • # Contributed equally.
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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