# Structural and molecular determinants of protein phosphatase 2A function in lung cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $624,772

## Abstract

Project Summary/Abstract
Lung cancer progression involves coordinate changes in both oncogene and tumor suppressor function. Protein
Phosphatase 2A (PP2A) is a tumor suppressor that is dysregulated and deactivated in lung cancer. PP2A is
inactivated through several mechanisms including somatic mutations, suppression of individual subunits,
increased expression of endogenous PP2A inhibitors and changes in post-translational modifications of the C
subunit. While several therapeutics have been developed to indirectly target PP2A, recent studies have
uncovered small molecules such as phenothiazines that directly activate PP2A. Nevertheless, because their
pronounced extrapyramidal and anti-cholinergic effects were severely dose limiting, further pursuit of
phenothiazines and related dibenzazepines for treatment of cancer seems unlikely. Our lab has reengineered
the tricyclic neuroleptics to decouple the CNS pharmacology from the anti-proliferative properties of this drug-
class. We have developed and characterized these small molecule activators of PP2A (SMAPs) as both chemical
tools to probe PP2A regulation and for the treatment of PP2A dependent diseases. Our combined structure-
function studies have revealed that SMAPs bind to PP2A in a way that protects the regulatory C-terminal tail of
the catalytic subunit and stabilizes the holoenzyme. Our goal is to define the SMAP induced alterations on PP2A
holoenzyme composition that promote the tumor suppressive properties of PP2A. We aim to identify the tumor
suppressive PP2A regulatory subunits enhanced by SMAPs in order to correlate treatment response to clinical
and genetic characteristics, and to aid in the design of more selective, next-generation SMAPs. In this project,
three robust aims are designed to assess how activation of PP2A using SMAPs represents an effective treatment
option for patients diagnosed with NSCLC. Aim 1 will structurally and functionally characterize the physiologic
and cancer-relevant posttranslational regulation of PP2A by SMAPs. We will investigate the SMAPs-specific
structural modulation of the PP2A holoenzyme by various, recurrent tumor derived mutations through coupling
methyl-PP2A-C antibody and immunoprecipitation-mass spectrometry based approaches to quantify post-
translational modification and PP2A activity. Aim 2 will discern how PP2A Aα mutations modulate the biological
activity of SMAPs. We will assess the functional role of common missense mutations in lung cancer by using
isogenic CRISPR/Cas9 cell lines to identify cellular phenotypes, subunit expression, SMAPs response, and
biological responses in nude mice. Aim 3 will determine combination treatment strategies to promote regression
of tumors in KRAS mutant lung cancer. We will examine rational treatment combinations with SMAPs based on
our studies demonstrating that protein phosphatase 2A (PP2A) activity defines the response of KRAS mutant
lung cancer cells across library of >200 kinase inhibitors. Collectivel...

## Key facts

- **NIH application ID:** 10444903
- **Project number:** 5R01CA240993-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Goutham Narla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $624,772
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444903

## Citation

> US National Institutes of Health, RePORTER application 10444903, Structural and molecular determinants of protein phosphatase 2A function in lung cancer (5R01CA240993-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444903. Licensed CC0.

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