SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

DOI PDF 1 Citations
  • Carmine Fedele
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Shuai Li
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Kai Wen Teng
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Connor J.R. Foster
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • David Peng
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Hao Ran
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Paolo Mita
    Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY 2
  • Mitchell J. Geer
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Takamitsu Hattori
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Akiko Koide
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Yubao Wang
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Kwan Ho Tang
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Joshua Leinwand
    S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY 4
  • Wei Wang
    S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY 4
  • Brian Diskin
    S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY 4
  • Jiehui Deng
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Ting Chen
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Igor Dolgalev
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Ugur Ozerdem
    Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, NY 5
  • George Miller
    S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY 4
  • Shohei Koide
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Kwok-Kin Wong
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1
  • Benjamin G. Neel
    Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY 1

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<jats:p>KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site–specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.</jats:p>

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