# Turn a brake back on: drugs that reactivate the PP2A phosphatase

Source: https://onco.cc/ideas/idea-bio1-pp2a-activators/  
OnCo record `idea-bio1-pp2a-activators` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Cells have an enzyme, PP2A, that removes the growth signals cancer relies on. Cancers switch it off. Drugs that switch it back on are an unusual and largely untried approach.

## Summary

PP2A is a tumour suppressor phosphatase that cancers inactivate through SET, CIP2A or subunit mutations. Small-molecule activators of PP2A (SMAPs) and the related class of phosphatase-directed compounds destabilise MYC and other oncoproteins by promoting their dephosphorylation and degradation. Activating an enzyme is harder than inhibiting one, which is why the class is underdeveloped.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: PP2A activation lowers MYC protein levels in tumours in vivo and synergises with MEK or CDK4/6 inhibition to produce durable regressions in models where either agent alone fails.
- Rationale: Phosphatase activation attacks the stability of undruggable oncoproteins indirectly; MYC's short half-life makes it especially sensitive to dephosphorylation at the residue that protects it from degradation.
- Proposed test: In vivo pharmacodynamics of a tool SMAP in KRAS-driven lung models, with MYC protein and phospho-site readouts, and a combination matrix with MEK inhibition.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- targets: [KRAS](https://onco.cc/targets/kras/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/), [Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib](https://onco.cc/key-papers/paper-kras-nsclc-j-clin-oncol-2005/), [Sotorasib for Lung Cancers with KRAS p.G12C Mutation](https://onco.cc/key-papers/paper-kras-nsclc-n-engl-j-med-2021/), [STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma](https://onco.cc/key-papers/paper-kras-nsclc-cancer-discov-2018/)

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