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Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy
Matheus Henrique Dias1, Anoek Friskes2, Siying Wang3
1Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Discovery
|March 27, 2024
Summary
Inhibiting protein phosphatase 2A (PP2A) and WEE1 together hyperactivates oncogenic pathways, causing cancer cell death. Acquired resistance paradoxically leads to tumor suppression, suggesting a novel therapeutic strategy for colon cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer homeostasis relies on balancing oncogenic signaling and stress responses.
- While oncogenic pathway inhibition is common, pathway overactivation can also be lethal.
- Protein phosphatase 2A (PP2A) inhibition can paradoxically activate oncogenic pathways and stress responses.
Purpose of the Study:
- To investigate the effects of PP2A inhibition on colon cancer cells.
- To identify synergistic drug combinations for cancer therapy.
- To explore the mechanisms of acquired resistance to novel cancer treatments.
Main Methods:
- Genetic and compound screens were employed.
- Inhibition of PP2A and WEE1 was tested in multiple cancer models.
- Patient-derived tumors were used for in vivo studies.
- Mechanisms of acquired resistance were analyzed.
Main Results:
- PP2A inhibition hyperactivated oncogenic pathways and stress responses in colon cancer.
- Combined inhibition of PP2A and WEE1 synergistically collapsed DNA replication and induced cell death.
- This combination suppressed patient-derived tumor growth in vivo.
- Acquired resistance to the combination therapy resulted in suppressed tumor formation in vivo.
Conclusions:
- Paradoxical activation of oncogenic signaling can lead to tumor suppression.
- Combined PP2A and WEE1 inhibition represents a potent anti-cancer strategy.
- Tumor-suppressive drug resistance may arise from loss of oncogenic signaling.
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