# Overcoming drug resistance using small molecule activators of protein phosphatase 2A

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $228,958

## Abstract

Uncontrolled cell proliferation resulting from aberrant activity of cell cycle proteins is a hallmark of cancer.
Overexpression of the mitogen sensor cyclin D1 is among the most frequent abnormalities in tumors, enhancing
the activity of cyclin dependent kinases 4 and 6 (CDK4/6) to drive G1→S phase progression and promote cell
survival and chemoresistance. Increased expression of D-type cyclins is required not only for tumorigenesis but
also for tumor maintenance and progression. Thus, aberrant cyclin D-CDK4/6 activity represents an actionable
target for cancer therapy and D-type cyclin function is among the top therapeutic targets for cancer management.
Inhibitors of CDK4/6 activity have shown promise in the clinic and palbociclib, abemaciclib, and ribociclib are
FDA-approved for use in patients. Several hundred clinical trials are currently ongoing to evaluate the antitumor
effects of these agents in a broad spectrum of cancer types. However, the therapeutic promise of CDK4/6
inhibitors is dampened by inevitable emergence of resistance. Recent seminal studies have identified a novel
mechanism of resistance to these agents mediated by deficiency of autophagy and beclin 1 regulator 1
(AMBRA1), an E3 ligase adaptor and master regulator of cyclin D1, D2, and D3 protein stability. Loss or mutation
of AMBRA1 is seen in a significant subset of human cancers, in association with poor patient survival. AMBRA1
deficiency promotes the accumulation of D-type cyclins, a hyperproliferative phenotype, and tumorigenesis, while
reducing the sensitivity of tumor cells to all three FDA-approved CDK4/6 inhibitors. Evidence that upregulation
of D-type cyclins and the formation of non-canonical cyclin D-CDK2 and p27-cyclin D-CDK4 complexes
underpins resistance to these agents forms the basis of this proposal. Strategies are proposed to explore the
mechanism-driven application of Small Molecule Activators of PP2A (SMAPs) for overcoming resistance to
CDK4/6 inhibitors in the context of AMBRA1 deficiency. SMAPs are a novel class of antitumor agents that
selectively activate a subset of PP2A holoenzymes for potent tumor suppression in a variety of cancer types.
This project builds on our discovery that SMAPs potently downregulate cyclins D1, D2 and D3 in all cell types
tested. Importantly, SMAPs act as AMBRA1-independent D-type cyclin ‘degraders,’ promoting rapid proteolysis
of these molecules via a proteasome-dependent mechanism that remains functional following loss of AMBRA1.
Based on these findings, we hypothesize that combining CDK4/6 inhibitor treatment with a SMAP ‘D-type cyclin
degrader’ will enhance antitumor activity and reverse resistance to CDK4/6 inhibitors driven by AMBRA1
deficiency. Proof-of-concept studies will be performed in two Specific Aims: (1) Explore the effects of combining
CDK4/6 inhibitors and SMAPS in the context of AMBRA1-deficiency, and (2) Evaluate the effects of SMAP-
CDK4/6 inhibitor combinations in tumor models in vivo. Importantly, in ...

## Key facts

- **NIH application ID:** 10513191
- **Project number:** 1R21CA273979-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Jennifer D. Black
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $228,958
- **Award type:** 1
- **Project period:** 2022-08-03 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513191

## Citation

> US National Institutes of Health, RePORTER application 10513191, Overcoming drug resistance using small molecule activators of protein phosphatase 2A (1R21CA273979-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10513191. Licensed CC0.

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