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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer
Pedro Torres-Ayuso1, John Brognard1
1Laboratory of Cell and Developmental Signaling, National Cancer Institute, Center for Cancer Research, Frederick, Maryland torresayusop2@nih.gov john.brognard@nih.gov.
Abstract:
Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SIGNIFICANCE STATEMENT: Protein kinases contribute to tumorigenesis through catalytic and noncatalytic mechanisms, and kinase gene amplifications are well described mechanisms of resistance to small molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting noncatalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.
Insights
Proteolysis-targeting chimeras offer a new way to fight cancer by degrading amplified kinases, overcoming resistance to traditional inhibitors and targeting non-catalytic functions.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Amplified pro-oncogenic kinases drive cancer cell proliferation and survival.
- Small molecule kinase inhibitors face resistance due to target amplification and non-catalytic kinase functions.
Purpose of the Study:
- To explore proteolysis-targeting chimeras (PROTACs) as a novel therapeutic strategy against amplified kinases.
- To address limitations of catalytic inhibitors in cancer therapy.
Main Methods:
- Discussion of the mechanisms of kinase amplification and resistance.
- Review of proteolysis-targeting chimera technology for protein degradation.
Main Results:
- PROTACs can effectively target amplified kinases by inducing their degradation.
- This approach overcomes resistance mechanisms associated with increased kinase expression.
- PROTACs can target both catalytic and non-catalytic functions of oncogenic kinases.
Conclusions:
- Proteolysis-targeting chimeras represent a promising therapeutic modality for cancers driven by amplified kinases.
- Degradation of kinases via PROTACs offers a strategy to overcome resistance and target non-catalytic oncogenic functions.
- Repurposing kinase inhibitors for PROTAC development may yield improved clinical benefits.
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