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EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling

Zhenyi Hu1,2, Po-Han Chen1,3,4, Wenxue Li5

  • 1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.

Science Advances
|March 27, 2024
PubMed

Insights

We developed phosphorylation targeting chimeras (PhosTACs) for targeted protein dephosphorylation. These molecules effectively inhibit kinases like EGFR, showing potential in cancer therapy by inducing apoptosis and reducing cell viability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Targeted protein dephosphorylation (TPDephos) is crucial for cellular signaling.
  • Receptor tyrosine kinases (RTKs) are key regulators of cell growth and are often dysregulated in cancer.
  • Existing RTK inhibitors (RTKIs) primarily block kinase activity, but dephosphorylation offers an alternative inhibition strategy.

Purpose of the Study:

  • To develop a novel heterobifunctional approach, phosphorylation targeting chimeras (PhosTACs), for targeted protein dephosphorylation.
  • To combine RTKI effects with active phosphatase-mediated dephosphorylation for dual kinase inhibition.
  • To investigate the efficacy of PhosTACs against epidermal growth factor receptor (EGFR) and their impact on cancer cell signaling and viability.

Main Methods:

  • Development of tyrosine phosphatase-based PhosTACs for targeted dephosphorylation.
  • Utilizing phosphoproteomic approaches to analyze proteome-wide signaling changes induced by PhosTACs.
  • Employing a covalent PhosTAC selective for mutated EGFR.
  • Assessing cancer cell viability and apoptosis induction in response to PhosTAC treatment.

Main Results:

  • Demonstrated effective epidermal growth factor receptor (EGFR) tyrosine dephosphorylation using PhosTACs.
  • Identified differential signaling pathway inhibition by PhosTACs compared to traditional TKIs like gefitinib.
  • Developed a covalent PhosTAC targeting mutated EGFR, showing inhibitory potential against dysregulated EGFR.
  • EGFR PhosTACs induced apoptosis and reduced cancer cell viability, particularly during prolonged treatment.

Conclusions:

  • PhosTACs represent a novel strategy for targeted protein dephosphorylation, offering a complementary approach to kinase inhibition.
  • This bifunctional molecule utility expands the scope of therapeutic strategies for cancers driven by RTK dysregulation.
  • PhosTACs demonstrate significant potential in modulating RTK activity and offer a promising avenue for cancer treatment.

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