# Translation Rewiring Underlines Drug Resistance to Lethal Targeted Ribosome Biogenesis Therapeutics in Cancer

> **NIH NIH K99** · JOHNS HOPKINS UNIVERSITY · 2024 · $109,489

## Abstract

Project Summary/Abstract
Increased ribosome biogenesis is a hallmark of cancer and reflects the increased and pervasive protein
synthetic needs of the cancer cells. Targeting this process by curbing the rate-limiting step, RNA polymerase I
(Pol I) transcription, using specific inhibitors abrogating this activity, is a promising strategy for cancer therapy.
BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and large-scale cancer cell line
screens demonstrated its potent efficacy across broad cancer lineages. However, a heterogeneous response
was observed emphasizing the presence of mechanisms dampening the therapeutic response. Genome-wide
positive selection CRISPR Cas9 knock-out screens were performed in human colorectal carcinoma cells to
identify genes that cause resistance to the selective inhibition of Pol I. The screens identified all key positive
regulators of the mTORC1 pathway accounting for the resistance. mTOR is a major driver of ribosome
biogenesis and cellular translational programs and considered essential for cancer growth. The inactivation of
mTOR as a resistance mechanism is counterintuitive, as this mechanism requires a reduced translational state
by the cancer cells and inactivation of two key pathways enabling protein synthesis. These unexpected
findings led to the hypothesis that cancer cells evade severe ribosome biogenesis stress by switching off
mTOR-dependent translational pathways. This premise stipulates that bypass mechanisms have evolved to
facilitate translation of essential proteins for survival and growth when cancer cells face obstacles in protein
translation. This concept will be tested using pharmacological and genetic approaches that block mTOR. The
goal of the project is to gain knowledge on the mechanisms that enable unabated ribosome translation in
cancer cells. The following aims will be implemented to achieve this goal: Aim 1. Identify genes driving
resistance to Pol I and translation inhibitor, Aim 2. Investigate the translational activity maintained under
translation stress in cancer cells and Aim 3. Identify the regulators of ribosome activity that support survival by
translation stress. By executing these aims we will gain knowledge how cancer cells survive severe
translational stress and the mechanisms of this escape. These studies will identify critical processes and
proteins required for survival and how their translation is maintained with limited ribosome numbers. These
findings have implications in therapeutic strategies that target ribosome biogenesis, protein synthesis and
translation and the approaches are designed to use this knowledge to develop new combination strategies to
overcome these resistance mechanisms.

## Key facts

- **NIH application ID:** 10808504
- **Project number:** 1K99CA279786-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Wenjun Fan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $109,489
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808504

## Citation

> US National Institutes of Health, RePORTER application 10808504, Translation Rewiring Underlines Drug Resistance to Lethal Targeted Ribosome Biogenesis Therapeutics in Cancer (1K99CA279786-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10808504. Licensed CC0.

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