Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in
Suhasini Joshi1, Erica DaGama Gomes1, Tai Wang1
1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Abstract:
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.
Insights
This study shows how to re-engineer cancer
Area of Science:
- Oncology
- Systems Biology
- Chemical Biology
Background:
- Cancer cell plasticity allows tumors to evade therapies.
- Protein-protein interaction networks (interactomes) are dynamic and crucial for cancer progression.
- Drug resistance remains a significant challenge in cancer treatment.
Purpose of the Study:
- To explore how manipulating protein connectivity can re-engineer cancer interactomes for therapeutic vulnerability.
- To demonstrate a novel pharmacologic approach to overcome cancer drug resistance.
Main Methods:
- Utilized chemical biology approaches for systems-level exploration of protein connectivity.
- Applied methods to pancreatic cancer cell lines, patient biospecimens, and xenografts in mice.
- Pharmacologically manipulated epichaperomes to control protein interactions in real-time.
Main Results:
- Demonstrated that cancer interactomes can be re-engineered to enhance vulnerability.
- Showed that pharmacologic manipulation of epichaperomes induces tumor interactome hyperconnectivity.
- This induced state suppresses alternative signaling and prevents rebound pathways.
Conclusions:
- Pharmacologic manipulation of epichaperomes primes tumors for enhanced therapeutic efficacy.
- This approach can make traditionally poorly performing therapeutics highly effective.
- Provides a paradigm to overcome drug resistance by targeting proteome-wide protein-protein interaction networks.
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