Related Experiment Video

Updated: Dec 6, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.5K

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Carmine Fedele1, Shuai Li1, Kai Wen Teng1

  • 1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY.

The Journal of Experimental Medicine
|October 12, 2020
PubMed

Insights

SHP2 inhibitors enhance KRAS G12C inhibitors' efficacy in KRASG12C-mutant cancers. This combination therapy shows promise for pancreatic ductal adenocarcinoma and non-small cell lung cancer, improving survival and immune response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Immunology

Background:

  • KRAS mutations are common in human cancers, making KRAS inhibition a key therapeutic goal.
  • KRAS G12C inhibitors (G12C-Is) target a specific KRAS mutation but face challenges with resistance.
  • SHP2, a protein tyrosine phosphatase, plays a role in signaling pathways relevant to cancer growth.

Purpose of the Study:

  • To investigate the efficacy of combining SHP2 inhibitors (SHP2-I) with G12C-Is.
  • To explore the mechanisms by which SHP2 inhibition affects KRAS signaling and cancer resistance.
  • To evaluate the impact of this combination on the tumor immune microenvironment and survival in preclinical models.

Main Methods:

  • Utilized novel affinity reagents to monitor KRASG12C activation and G12C-I engagement.
  • Assessed the effects of SHP2-I/G12C-I combination in vitro, in xenograft models, and in syngeneic models of KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC).
  • Analyzed changes in the tumor immune microenvironment, including myeloid suppressor cells and CD8+ T cells, and assessed tumor angiogenesis.

Main Results:

  • SHP2 inhibition increased KRAS-GDP occupancy, enhancing G12C-I efficacy.
  • The combination abrogated RTK feedback signaling and adaptive resistance to G12C-Is.
  • SHP2-I/G12C-I treatment modulated the immune microenvironment, decreased tumor angiogenesis, and sensitized tumors to PD-1 blockade.
  • SHP2 inhibition was crucial for PDAC regression and immune microenvironment remodeling.

Conclusions:

  • SHP2-I/G12C-I combination therapy provides a substantial survival benefit in PDAC and NSCLC models.
  • SHP2 inhibition overcomes resistance mechanisms and enhances the anti-tumor activity of G12C-Is.
  • This combination strategy presents a promising therapeutic approach and suggests further combination possibilities.

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.3K
Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis07:26

Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis

Published on: January 31, 2025

891

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
10.9K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.4K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.4K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.9K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.0K