# Protein Tyrosine Dephosphorylation & Signal Transduction

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2022 · $753,531

## Abstract

PROJECT SUMMARY/ ABSTRACT
The first drugs directed against protein tyrosine kinases (PTKs) have now entered the market and represent
breakthroughs in the treatment of cancer; however, challenges remain, including the fact that patients develop
resistance to such drugs. Alternative approaches, to target simultaneously different signaling enzymes and
events, are required. The protein tyrosine phosphatases (PTPs), which work in combination with the PTKs, have
been garnering attention as potential therapeutic targets. Despite major programs in industry focused on
developing small molecule PTP inhibitors, technical challenges arising from the chemical properties of the PTP
active site have frustrated such efforts. Consequently, they remain a largely untapped resource for drug
development. Nevertheless, the extensive biological validation of PTPs emphasizes the importance of
discovering new approaches to inhibitor development. This grant, currently in Year 28, focuses on a functional
analysis of specific PTPs in models of cancer. The hypothesis to be tested is that PTPs function as specific
regulators of tyrosine phosphorylation-dependent signaling pathways and thus manipulation of their function in
cell and animal models will reveal new insights into the critical signaling events that underlie the disease. The
overall goal is to define functional links between particular PTPs and specific signaling pathways in cancer, with
a view to establishing how disruption of such functions affects the etiology of the disease and to reveal novel
therapeutic targets from among the PTPs themselves or from the signaling pathways they regulate. In the
previous funding period, major breakthroughs were achieved in several aspects of the project: (1) New and
improved allosteric inhibitors of PTP1B, including molecules that chelate copper specifically, were developed,
creating opportunities to exploit a novel vulnerability in cancer; (2) Identification of PTP1B inhibitors that are
cytotoxic to Herceptin-resistant cells; (3) Demonstration that PTP1B inhibitors prevent fatality in the TRALI model
of Acute Respiratory Distress Syndrome, attenuating neutrophil activation and formation of NETs, suggesting
novel opportunities for therapeutic intervention in cancer; (4) Integration of BioID MS with substrate-trapping
mutant PTPs to enhance substrate trapping technology and generate new insights into the function of PTP1B in
Herceptin-resistant cells, illustrating an approach can now be applied to the PTP family as a whole to validate
new therapeutic targets. Building on the unique and innovative approaches developed during previous funding
periods, this proposal assembles a strong team of collaborators to address the following Specific Aims, which
represent a logical development of progress to date: 1: To define the mechanism by which PTP1B represents a
point of vulnerability in Herceptin-resistant cells. 2: To validate copper chelation and PTP1B inhibition as a new
avenue to ca...

## Key facts

- **NIH application ID:** 10436362
- **Project number:** 5R01CA053840-30
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** NICHOLAS K TONKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $753,531
- **Award type:** 5
- **Project period:** 1991-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436362

## Citation

> US National Institutes of Health, RePORTER application 10436362, Protein Tyrosine Dephosphorylation & Signal Transduction (5R01CA053840-30). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10436362. Licensed CC0.

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