# Smoothened as a Novel Signal Stabilization Scaffold in Doxorubicin Resistance

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $470,533

## Abstract

Smoothened as a Novel “Signal Stabilization Scaffold” in Doxorubicin Resistance
Doxorubicin (DXR) is among the most widely used therapeutics in cancer treatment. However, combined with
its cardiotoxicity, the need for higher dosing due to drug resistance is a major challenge in treatment. Diffuse B-
Cell Lymphoma (DLBCL) is the most common lymphoma in adults, and DXR resistance is the predominant
limiting factor for the successful use of current anthracycline based standard therapy (CHOP). Enhanced AKT
signaling is known to be associated with loss of DXR sensitivity, and traditionally, mechanisms that directly act
on its phosphorylation/dephosphorylation have been the main focus of research. More recently, competing
AKT ubiquitination modes have emerged as a critical factor that balances degradation (UB-K48 linkage) versus
membrane recruitment, Ser/Thr phosphorylation and activation (UB-K63 linkage). Membrane localized pAKT is
represents the most potent oncogenic signal. We found that TRAF6, a (K63)E3-ligase, is responsible for
regulating pAKT stability and function in DLBCL. Moreover, we observed for the first time that this mechanism
is dependent on the seven transmembrane spanning receptor “Smoothened” (SMO). SMO is localized in raft
microdomains, recruits TRAF6, initiates TRAF6 auto stabilization and activation, and thereby enhances
signaling that is needed for DXR resistance. This novel role of SMO goes beyond its canonical role in
Hedgehog signaling and is reflected in elevated SMO expression in samples from patients with DXR resistant
DLBCL. Ectopic SMO expression or SMO knockdown decrease or increase DXR sensitivity respectively in
lymphoma cell lines. In this proposal, we will dissect the regions of SMO that are needed for this novel function
and identify the interaction partners that are assembled for this raft-localized signal stabilization function. In
addition, we will use a patient derived xenograft mouse model to evaluate the contribution of SMO to
chemoresistance and evaluate the utility of adding existing SMO inhibitors to the current chemotherapy
regimens to reverse resistance.

## Key facts

- **NIH application ID:** 10377576
- **Project number:** 5R01CA222918-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** RALF LANDGRAF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $470,533
- **Award type:** 5
- **Project period:** 2019-04-03 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377576

## Citation

> US National Institutes of Health, RePORTER application 10377576, Smoothened as a Novel Signal Stabilization Scaffold in Doxorubicin Resistance (5R01CA222918-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10377576. Licensed CC0.

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