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The JAK-STAT Signaling Pathway01:20

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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...
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Sidestepping SHP2 inhibition.

Bogdan Popescu1,2, Kevin Shannon3,4

  • 1Department of Medicine, University of California, San Francisco , San Francisco, CA, USA.

The Journal of Experimental Medicine
|March 7, 2023
PubMed
Summary
This summary is machine-generated.

Researchers identified new ways cancer cells become resistant to SHP2 inhibitors, a promising new cancer therapy. This study used a genome-wide CRISPR screen to uncover these resistance mechanisms, paving the way for more effective treatments.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hyperactive Ras/Mitogen Activated Protein Kinase (MAPK) signaling is a key driver in many cancers.
  • Allosteric SHP2 inhibitors represent a novel therapeutic strategy targeting this pathway.
  • Understanding resistance mechanisms is crucial for optimizing SHP2 inhibitor efficacy.

Purpose of the Study:

  • To identify novel mechanisms of adaptive resistance to pharmacologic SHP2 inhibition.
  • To explore the genetic basis of resistance using a genome-wide screening approach.

Main Methods:

  • Utilized a genome-wide CRISPR/Cas9 knockout screen.
  • Investigated adaptive resistance to allosteric SHP2 inhibitors in cancer models.

Main Results:

  • Uncovered previously unknown genetic factors contributing to resistance against SHP2 inhibitors.
  • Identified novel pathways involved in the adaptive response to SHP2 blockade.

Conclusions:

  • The findings reveal new insights into the complex mechanisms of acquired resistance to SHP2-targeted therapies.
  • This research may inform the development of combination strategies to overcome or prevent resistance.