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Updated: Jan 18, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
A kinome inhibitor screen implicates adhesion and growth factor signaling in cellular recovery after caspase
Maddalena Nano1,2,3, Jacob Harwood1,2,3, Gabriel Lukaszewicz2
1These authors contributed equally to this work.
Abstract:
Apoptosis is a common form of regulated cell death and requires cysteine-aspartic proteases called effector caspases. Caspase activation triggers positive feedback, leading to the idea that apoptosis is irreversible. However, we and others have demonstrated that cancer cells can survive effector caspase activation and become more aggressive and drug-resistant as a result. Despite the profound implications of apoptotic reversal, also known as anastasis, for both regenerative medicine and cancer therapy, the molecular pathways that enable cells to survive executioner caspase activation remain largely unmapped. To systematically dissect this phenomenon, we developed a quantitative screening platform that combines inducible caspase activation with kinome-wide pharmacological profiling. This approach uniquely allowed us to: (1) identify pharmacological modulators of post-caspase survival, (2) identify specific kinases regulating post-caspase survival, and (3) distinguish general toxicity from anastasis effects. This approach implicated regulators of cell adhesion and the cytoskeleton, consistent with the known rounding of apoptotic cells and respreading during recovery. Growth factor signaling also emerged from the analysis. In addition to its expected effects on unstressed cells, fetal bovine serum markedly increased anastasis. Some growth factor combinations were more effective than individual ones at recapitulating the serum effect. Similarly, pleiotropic kinase inhibitors were generally more effective than selective ones. Nevertheless, selective Rho kinase inhibition significantly enhanced anastasis whereas Akt inhibition impaired it, suggesting that these kinases serve as central nodes that integrate multiple upstream inputs. Beyond identifying specific kinase targets, our work provides a framework for 'anti-anastasis' therapies that could prevent cancer cell recovery after chemotherapy.
Insights
Cancer cells can survive apoptosis, a process called anastasis, becoming more aggressive. This study identifies key kinases and pathways involved in this survival, offering targets for anti-cancer therapies to prevent cell recovery.
Area of Science:
- Cell Biology
- Cancer Research
- Pharmacology
Background:
- Apoptosis, or programmed cell death, is typically considered irreversible due to effector caspase activation.
- However, cancer cells can survive effector caspase activation, a phenomenon known as anastasis, leading to increased aggressiveness and drug resistance.
- The molecular mechanisms underlying anastasis remain largely uncharacterized, hindering the development of effective cancer therapies.
Purpose of the Study:
- To systematically identify molecular pathways and kinases that regulate cancer cell survival after effector caspase activation (anastasis).
- To develop a screening platform for discovering modulators of post-caspase survival and distinguishing anastasis from general toxicity.
- To provide a framework for developing 'anti-anastasis' therapies to prevent cancer cell recovery.
Main Methods:
- Developed a quantitative screening platform combining inducible caspase activation with kinome-wide pharmacological profiling.
- Utilized the platform to identify pharmacological modulators and specific kinases regulating post-caspase survival.
- Differentiated between general toxicity and true anastasis effects.
Main Results:
- Identified regulators of cell adhesion, cytoskeleton, and growth factor signaling pathways involved in anastasis.
- Fetal bovine serum significantly enhanced anastasis, with specific growth factor combinations proving more effective.
- Rho kinase inhibition enhanced anastasis, while Akt inhibition impaired it, highlighting their roles as central regulatory nodes.
Conclusions:
- Anastasis is a regulated process influenced by cell adhesion, cytoskeleton dynamics, and growth factor signaling.
- Specific kinases, such as Rho kinase and Akt, play critical roles in integrating signals that promote or inhibit anastasis.
- The findings provide a foundation for developing novel anti-anastasis therapies to improve cancer treatment outcomes by preventing cancer cell survival and recurrence.
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