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SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2020
- Publisher :
- Rockefeller University Press, 2020.
-
Abstract
- G12C inhibitors (G12C-Is) have significant but limited efficacy in KRAS-mutant malignancies, mostly due to “adaptive resistance.” Combining SHP2 inhibitor (SHP2-I) with G12C-I abrogates adaptive resistance; evokes beneficial, tumor-specific changes in the immune microenvironment; and potentiates PD-1 blockade. SHP2-I also has direct, context-dependent effects on tumor vasculature.<br />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.
- Subjects :
- 0301 basic medicine
Lung Neoplasms
Myeloid
endocrine system diseases
Immunology
Mutation, Missense
Protein Tyrosine Phosphatase, Non-Receptor Type 11
medicine.disease_cause
Article
law.invention
Proto-Oncogene Proteins p21(ras)
Mice
03 medical and health sciences
0302 clinical medicine
law
Carcinoma, Non-Small-Cell Lung
Tumor Microenvironment
medicine
Animals
Immunology and Allergy
Enzyme Inhibitors
Solid Tumors
Mice, Knockout
Tumor microenvironment
Oncogene
Chemistry
Cancer
medicine.disease
digestive system diseases
In vitro
Pancreatic Neoplasms
030104 developmental biology
medicine.anatomical_structure
Amino Acid Substitution
030220 oncology & carcinogenesis
Tumor immunology
Cancer research
Suppressor
KRAS
CD8
Carcinoma, Pancreatic Ductal
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 218
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....7224c67e8ce4af58bbaecacab6907000