Drug Resistance

Targeting Ribosome Biogenesis in Cancer

Increased ribosome biogenesis is a fundamental hallmark of cancer. Targeting this hyperactive process with RNA polymerase I (Pol I) inhibitors—such as the first-in-class small molecule BMH-21—represents a highly promising therapeutic strategy across multiple tumor types. However, cancer cells often exhibit diverse and heterogeneous responses to these treatments, underscoring a critical need to understand the precise molecular mechanisms that drive drug resistance.

Uncovering Mechanisms of Therapeutic Resistance

To decode these cellular survival strategies, our laboratory utilizes genome-wide CRISPR-Cas9 positive selection screens to identify the master genetic regulators that modulate how cancer cells respond to Pol I inhibition. By interrogating human cancer models, we have successfully mapped high-confidence genetic pathways that dictate therapeutic sensitivity and resistance, operating independently of common tumor suppressors like p53.

The Role of Compensatory Translation

Through integrated approaches utilizing polysome profiling, Ribo-seq, and RNA-seq, we have discovered exactly how resistant cancer cells mount a defense against transcription stress. Under the severe ribosome biogenesis defect caused by Pol I inhibitors, these resilient cells evoke a compensatory, selective translation of specific ribosomal proteins. By elevating the translation efficiency of these key mRNAs, cancer cells can maintain enough translational capacity to bypass the Pol I inhibition and survive.

Future Directions

Our ongoing research focuses on how this maintenance of specific translational capacity directly fuels treatment resistance. By understanding the complex cellular workarounds that cancer cells use to survive severe biogenesis defects, we aim to uncover unforeseen vulnerabilities and establish the foundation for powerful, rationally designed drug combinations in the clinic.