A PP2A molecular glue overcomes ras/mapk inhibitor resistance in kras-mutant non-small cell lung cancer

Brynne Raines; Stephanie Tseng-Rogenski; Amanda C. Dowdican; Irene Peris; Matthew Hinderman; Kaitlin P. Zawacki; Kelsey Barrie; Gabrielle Hodges Onishi; Alexander M. Dymond; Tahra K. Luther; Sydney Musser; Behirda Karaj Majchrowski; J. Chad Brenner; Aqila Ahmed; Derek J. Taylor; Caitlin M. O'Connor; Goutham Narla

doi:10.1172/JCI193790

¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

Find articles by Musser, S. in: PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

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¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

Find articles by O'Connor, C. in: PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

²Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

³Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States of America

⁴Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

Find articles by Narla, G. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI193790.
Copyright © 2025, Raines et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 14, 2025 - Version history

The effectiveness of RAS/MAPK inhibitors in treating metastatic KRAS-mutant NSCLC is often hindered by the development of resistance driven by disrupted negative feedback mechanisms led by phosphatases like PP2A. PP2A is frequently suppressed in lung cancer to maintain elevated RAS/MAPK activity. Despite its established role in regulating oncogenic signaling, targeting PP2A with RAS/MAPK to prevent resistance has not been previously demonstrated. In this study, we aimed to establish a treatment paradigm by combining a PP2A molecular glue with a RAS/MAPK inhibitor to restore PP2A activity and counteract resistance. We demonstrated that KRASG12C and MEK1/2 inhibitors disrupted PP2A carboxymethylation and destabilized critical heterotrimeric complexes. Furthermore, genetic disruption of PP2A carboxymethylation enhanced intrinsic resistance to MEK1/2 inhibition both in vitro and in vivo. We developed RPT04402, a PP2A molecular glue that selectively stabilizes PP2A-B56α heterotrimers. In both commercial cell lines and a patient-derived model, combining RPT04402 with a RAS/MAPK inhibitor slowed proliferation and enhanced apoptosis. In mouse xenografts, this combination induced tumor regressions, extended median survival, and delayed the onset of treatment resistance. These findings highlight that promoting PP2A stabilization and RAS/MAPK inhibition presents a promising therapeutic strategy to improve treatment outcomes and overcome resistance in metastatic KRAS-mutant NSCLC.

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A PP2A molecular glue overcomes ras/mapk inhibitor resistance in kras-mutant non-small cell lung cancer

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