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A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non-small cell lung cancer

Brynne Raines1,2,3, Stephanie Tseng-Rogenski2, Amanda C Dowdican2,3

  • 1Cellular and Molecular Biology Program and.

The Journal of Clinical Investigation
|October 14, 2025
PubMed

Insights

Combining a PP2A molecular glue with RAS/MAPK inhibitors shows promise for treating KRAS-mutant non-small cell lung cancer (NSCLC). This approach restores PP2A activity, overcoming resistance and improving treatment outcomes in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RAS/MAPK pathway inhibitors are crucial for metastatic KRAS-mutant non-small cell lung cancer (NSCLC).
  • Resistance to these inhibitors often arises from disrupted negative feedback loops involving phosphatases like PP2A, which is suppressed in lung cancer.
  • Targeting PP2A in conjunction with RAS/MAPK inhibition to prevent resistance has not been previously explored.

Purpose of the Study:

  • To investigate a novel therapeutic strategy combining a PP2A molecular glue with RAS/MAPK inhibitors.
  • To restore PP2A activity and counteract resistance mechanisms in KRAS-mutant NSCLC.
  • To evaluate the efficacy of this combination therapy in preclinical models.

Main Methods:

  • Assessed the impact of KRASG12C and MEK1/2 inhibitors on PP2A carboxymethylation and heterotrimeric complex stability.
  • Utilized genetic disruption of PP2A carboxymethylation to study resistance to MEK1/2 inhibition.
  • Developed and tested RPT04402, a PP2A molecular glue, in combination with a RAS/MAPK inhibitor.
  • Evaluated the combination therapy's effects on cell proliferation, apoptosis, tumor regression, survival, and resistance in vitro and in vivo.

Main Results:

  • RAS/MAPK inhibitors were found to disrupt PP2A carboxymethylation and destabilize PP2A heterotrimeric complexes.
  • Genetic impairment of PP2A carboxymethylation led to increased resistance to MEK1/2 inhibition.
  • The PP2A molecular glue RPT04402 selectively stabilized PP2A-B56α heterotrimers.
  • Combination therapy with RPT04402 and a RAS/MAPK inhibitor reduced proliferation, enhanced apoptosis, induced tumor regressions, extended survival, and delayed resistance in preclinical models.

Conclusions:

  • Restoring PP2A activity through stabilization with a molecular glue, alongside RAS/MAPK inhibition, is a viable strategy.
  • This combination therapy effectively overcomes resistance mechanisms in KRAS-mutant NSCLC.
  • The findings support the development of PP2A-stabilizing agents as a promising approach to improve treatment outcomes for NSCLC patients.
Keywords:
Cell biologyDrug therapyLung cancerOncologyTumor suppressors

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