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
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
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Research Article Cell biology Oncology

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

Abstract

The effectiveness of RAS/MAPK inhibitors in treating metastatic KRAS-mutant non–small cell lung cancer (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 commercial cell lines and in 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.

Authors

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

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Figure 6

RPT04402 delays RAS/MAPKi-induced acquired resistance in KRAS-mutant NSCLC in vivo.

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RPT04402 delays RAS/MAPKi-induced acquired resistance in KRAS-mutant NSC...
(A) Tumor growth curves of A549 CDX mice treated with vehicle (n = 9), trametinib (1 mg/kg QD, n = 10), RPT04402 (30 mg/kg QD, n = 8), or the combination (n = 7). TGI was assessed at day 48; 2-way ANOVA with Tukey’s post hoc analysis was used for statistical significance. Statistical comparisons for vehicle versus all treatments: ***P ≤ 0.001, ****P ≤ 0.0001; trametinib versus combination: ##P ≤ 0.01. (B) Waterfall plot displaying the percentage change in tumor volume at day 48. RECIST criteria were used to categorize responses (PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response). (C) Kaplan-Meier survival curves for A549 CDX. Median survival and increase in lifespan (increased lifespan) are shown; significance was determined using the log-rank (Mantel-Cox) test comparisons: vehicle versus all treatments: ****P ≤ 0.0001; trametinib versus combination: ##P ≤ 0.01. (D) Tumor growth curve for NCI-H358 CDX mice treated with vehicle (n = 8), adagrasib (30 mg/kg QD, n = 9), RPT04402 (10 mg/kg QD, n = 8), and the combination (n = 9). TGI was assessed at day 29. Statistical comparisons for vehicle versus all treatments: **P ≤ 0.01, ***P ≤ 0.0001; adagrasib versus combination, #P ≤ 0.05. (E) Waterfall plot displaying the percentage change in tumor volume on day 29, categorized by RECIST. (F) Kaplan-Meier curves for NCI-H358 CDX with median survival and increased lifespan indicated. Log-rank test comparisons: vehicle versus all treatments, **P ≤ 0.01; adagrasib versus combination, #P = 0.053.