{"entity":{"id":"idea-bio1-pp2a-activators","kind":"idea","name":"Turn a brake back on: drugs that reactivate the PP2A phosphatase","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["kras"],"drugs":[],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer","paper-kras-nsclc-n-engl-j-med-2021","paper-kras-nsclc-cancer-discov-2018","paper-kras-nsclc-j-clin-oncol-2005"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":7},"route":"/ideas/idea-bio1-pp2a-activators/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"},{"id":"paper-kras-nsclc-j-clin-oncol-2005","kind":"paper","name":"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","route":"/key-papers/paper-kras-nsclc-j-clin-oncol-2005/"},{"id":"paper-kras-nsclc-n-engl-j-med-2021","kind":"paper","name":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","route":"/key-papers/paper-kras-nsclc-n-engl-j-med-2021/"},{"id":"paper-kras-nsclc-cancer-discov-2018","kind":"paper","name":"STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma","route":"/key-papers/paper-kras-nsclc-cancer-discov-2018/"}]}}