2. Academic Validation
  3. Genetic mechanisms of resistance to targeted KRAS inhibition

Genetic mechanisms of resistance to targeted KRAS inhibition

  • bioRxiv. 2025 Aug 4:2025.08.04.668444. doi: 10.1101/2025.08.04.668444.
Bianca J Diaz 1 2,  Max Kops 1 2,  Sara Bernardo 1,  Henri Schmidt 3,  Elizabeth Grankowsky 1,  Adrian Vega 1,  Chen Zhang 4,  Matthew Bott 5,  Maria Skamagki 5,  Aidan Tomlinson 6,  Nicole A Vita 6,  Alyna Katti 6,  Mark P Labrecque 6,  Ida Aronchik 6,  Mallika Singh 6,  Lukas E Dow 1 2 7 8
Affiliations

Affiliations

  • 1 Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY.
  • 2 Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY.
  • 3 Department of Computer Science, Princeton University, Princeton, NJ.
  • 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
  • 5 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 6 Revolution Medicines, Inc., Redwood City, CA.
  • 7 Department of Medicine, Weill Cornell Medicine, New York, NY.
  • 8 Department of Biochemistry, Weill Cornell Medicine, New York, NY.
PMID: 40799582 DOI: 10.1101/2025.08.04.668444
Abstract

KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung Cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly understood. Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), Ras(ON) G12C-selective tri-complex inhibitor (RMC-4998), and Ras(ON) multi-selective tri-complex inhibitor (RMC-7977). Using both a saturation Kras tiling approach and cancer-associated mutation library, we identify common and compound-selective second-site resistance mutations in Kras, as well as gain-of-function and loss-of-function variants across cancer-associated genes that rewire signaling networks in a context-dependent manner. Notably, we identify a recurrent missense mutation in capicua (Cic), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NFκB signaling in CIC-mutant cells can resensitize them to Ras pathway inhibition and overcome resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.96%, KRAS G12C Inhibitor
    Ras