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Updated: Feb 20, 2026
SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer
Liqin Wang1, Rodrigo Leite de Oliveira1, Cun Wang1
1Division of Molecular Carcinogenesis, Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Abstract:
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the BCL2 family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.
Insights
Scientists identified ways to induce senescence, a cancer cell growth arrest, in melanoma and lung cancer. Senescent cells became vulnerable to ABT263, suggesting a two-drug cancer treatment strategy.
Area of Science:
- Oncology
- Cellular Biology
- Cancer Research
Background:
- Cellular senescence is a state of irreversible proliferation arrest, often triggered by stress.
- While senescence can be a tumor-suppressive mechanism, the specific triggers for senescence induction in cancer cells remain largely unknown.
- Understanding these triggers is crucial for developing novel cancer therapies.
Purpose of the Study:
- To identify genetic and chemical targets that induce senescence in cancer cells.
- To explore the vulnerabilities of drug-induced senescent cancer cells.
- To propose a novel therapeutic strategy for cancer treatment.
Main Methods:
- Utilized functional genetic and compound screens in cancer cells engineered with a senescence reporter.
- Investigated the role of the SWI/SNF component SMARCB1 in melanoma senescence.
- Screened for compounds that induce senescence in RAS-mutant lung cancer.
- Assessed the sensitivity of senescent cancer cells to the BCL2 family inhibitor ABT263.
Main Results:
- Suppression of SMARCB1 induced senescence in melanoma via robust MAP kinase pathway activation.
- Aurora kinase inhibitors were identified as potent inducers of senescence in RAS-mutant lung cancer.
- Both senescent melanoma and lung cancer cells exhibited increased sensitivity to ABT263.
- This suggests a potential therapeutic window for targeting senescent cancer cells.
Conclusions:
- Targeting SMARCB1 or using aurora kinase inhibitors can effectively induce senescence in specific cancer types.
- Senescent cancer cells become susceptible to BCL2 family inhibitors like ABT263.
- A sequential 'one-two punch' approach, inducing senescence followed by targeted killing, shows promise for cancer treatment.
