Related Experiment Video
Updated: Jul 15, 2025
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities
Liang Chang1,2,3, Nancy Y Jung1, Adel Atari1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract:
The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
Insights
Activating specific cancer pathways can create vulnerabilities. This study identified new dependencies, particularly in colorectal cancers, where pathway activation yielded significant anti-tumor effects.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer therapy traditionally targets pathway inhibition.
- Conditional pathway activation as a vulnerability source is underexplored.
- Systematic identification of gene-activation-induced lethality is needed.
Purpose of the Study:
- To systematically identify context-specific gene-activation-induced lethalities in cancer.
- To explore the pan-cancer vulnerability landscape through pathway activation.
Main Methods:
- Developed a high-throughput method for simultaneous gain-of-function genetic perturbations across ~500 barcoded cancer cell lines.
- Queried cancer vulnerability by activating ten key pathway nodes.
- Validated findings in xenograft and patient-derived organoid models.
Main Results:
- Revealed selective activation dependencies of MAPK and PI3K pathways linked to specific biomarkers.
- Discovered novel pathway hyperactivation dependencies in APC-mutant colorectal cancers.
- Demonstrated that WNT pathway activation via APC knockdown or β-catenin overexpression induced robust anti-tumor effects.
Conclusions:
- Identified a new class of conditional gene-activation dependencies in cancer.
- Highlights pathway activation as a potential therapeutic strategy.
- Suggests biomarker-driven approaches for targeted pathway activation therapies.
Related Concept Videos
01:16In-vitro Mutagenesis
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:55Synthetic Biology
Golden rice
Golden rice is a genetically modified...