# Targeted inhibition of ribosomal RNA synthesis in LKB1-deficient cancers

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $356,850

## Abstract

The presence of abnormal nucleoli has been used as a marker for aggressive cancers for over 100 years. The
nucleolus is the location for ribosomal RNA (rRNA) biogenesis, which requires approximately 80% of the
energy generated by cancer cells. The first step of rRNA biogenesis is the transcription of pre-rRNA, which
involves the binding of TIF-IA/RNA Pol I to the UBF/SL1 complex at the rDNA promoter. Many oncogenic
mutations, such as Myc amplification and AKT activation, have been associated with the promotion of pre-
rRNA synthesis. However, as pre-rRNA synthesis is a housekeeping function, direct targeting of pre-rRNA
synthesis for cancer therapy has been controversial.
Lung cancer is the leading cause of cancer death in the United States, with the majority of patients having non-
small cell lung cancer (NSCLC). The 3rd most commonly mutated gene in NSCLC adenocarcinoma is the
serine/threonine kinase LKB1 (STK11), and ~25,000 patients have mutations in LKB1. We recently discovered
that LKB1 protein promotes TIF-IA-mediated pre-rRNA synthesis when intracellular UTP is down-regulated,
and LKB1-mutant cells lacking such regulation are prone to apoptosis. Based upon these preliminary and
published data, we hypothesize that LKB1 inactivation in NSCLC represents a unique acquired tumor
vulnerability that can be targeted because cells deficient in LKB1 have lost the ability to promote TIF-IA
mediated transcription. The objectives of this proposal are i) to define the molecular mechanism underlying the
regulation of TIF-IA mediated pre-rRNA transcription by LKB1, and ii) to determine whether pharmacologic
inhibition of de novo uridine monophosphate (UMP) synthesis can specifically suppress LKB1-mutant lung
tumors in vivo. These objectives will be met by performing preclinical mouse trials in a unique and clinically-
relevant genetically-engineered mouse model (GEMM) and patient derived xenograft (PDX) models to
examine inhibition of de novo UMP synthesis by leflunomide as a strategy for inhibiting LKB1-mutant tumors.
Since leflunomide is a commonly used clinical agent, we propose that the data from this study will provide a
rational foundation to develop a future clinical trial with this inhibitor specifically targeting patients with LKB1
loss-of-function mutations.

## Key facts

- **NIH application ID:** 10127587
- **Project number:** 5R01CA203928-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Wei Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127587

## Citation

> US National Institutes of Health, RePORTER application 10127587, Targeted inhibition of ribosomal RNA synthesis in LKB1-deficient cancers (5R01CA203928-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127587. Licensed CC0.

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