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Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells
Garry L Coles1, Sandra Cristea1, James T Webber2
1Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Cancer Cell
|June 13, 2020
Summary
Protein kinase A (PKA) is a key driver in small cell lung cancer (SCLC). Inhibiting PKA or activating PP2A suppresses SCLC growth, while GNAS activation promotes it, revealing a new therapeutic target axis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options.
- Identifying novel signaling pathways is crucial for developing targeted therapies in SCLC.
Purpose of the Study:
- To identify active kinases in SCLC using unbiased profiling.
- To investigate the role of protein kinase A (PKA) in SCLC development and propagation.
- To explore the GNAS/PKA/PP2A signaling axis as a potential therapeutic target in SCLC.
Main Methods:
- Unbiased kinase profiling to identify active kinases in SCLC.
- Genetic and pharmacological inhibition of PKA activity.
- Activation of PP2A phosphatase to study its effect on SCLC.
- Phosphoproteomic and broad proteomic analyses to identify PKA substrates and signaling networks.
- In vitro cell culture and in vivo SCLC expansion models.
- SCLC stem cell propagation studies using transplantation models.
Main Results:
- Protein kinase A (PKA) was identified as an active kinase in SCLC.
- Inhibition of PKA activity suppressed SCLC expansion in vitro and in vivo.
- Activation of the PP2A phosphatase also suppressed SCLC growth.
- GNAS, a PKA activator, was found to be genetically activated in a subset of SCLC and promoted SCLC development.
- PKA activity was essential for the propagation of SCLC stem cells.
- Numerous PKA substrates and mechanisms of action were identified through phosphoproteomic analysis.
Conclusions:
- The GNAS/PKA/PP2A signaling axis represents a critical pathway in SCLC.
- Targeting PKA or modulating PP2A activity holds therapeutic potential for SCLC.
- Unbiased proteomic analysis can uncover novel targetable signaling networks in recalcitrant cancers like SCLC.
