RNA Surveillance Tracks Down and Degrades Cancer-Causing Molecules

Modulating the RNA surveillance network represents an unexplored area of drug discovery in cancer.

Therapeutics

Project Overview

The loss of RNA quality control is a cancer driver, yet little is known about the mechanisms involved in the RNA surveillance network that lead to an overaccumulation of abnormal RNAs.
Dana-Farber proposes a first-in-class method for targeting and degrading aberrant RNAs in a form of melanoma with potential applicability to other tumors.
This RNA surveillance platform is available for sponsored research opportunities to identify compounds for therapeutic targeting of the RNA surveillance system.

Technology

RNA surveillance is a critical cellular process that ensures the integrity of RNA transcripts before they are translated into proteins. If not identified and cleared from the cell’s nucleus, an overabundance of irregular RNAs can contribute to cancer development.

Cells have mechanisms for surveilling and destroying aberrant RNA. The nuclear RNA exosome is a key player in this surveillance system, monitoring the cell for incorrect RNAs in the nucleus―and destroying them to prevent their translation.

However, mutations in the components of the RNA surveillance machinery can disrupt this process, leading to the accumulation of aberrant RNAs, which can act as oncogenic drivers.

Megan Insco, MD, PhD has been at the forefront of research in RNA surveillance, particularly in the context of cancer. Her work has revealed that mutations in RNA surveillance pathways are often selected in cancer cells, as these mutations allow for the survival of aberrant RNAs that contribute to cancer progression. She has identified novel nuclear RNA surveillance pathways that specifically target problematic RNAs.

One significant discovery by the Insco lab is the role of Cyclin-dependent kinase 13 (CDK13) in RNA surveillance. CDK13 is a tumor suppressor that, when functioning normally, activates the RNA surveillance machinery to degrade ptRNAs in the nucleus. However, mutated CDK13 no longer can activate the RNA surveillance and degradation pathways, leading to the stabilization and translation of ptRNAs, and resulting in more aggressive forms of melanoma.

The team’s research has shown that forced expression of aberrant RNAs can accelerate melanoma development in zebrafish models, highlighting the oncogenic potential of these RNAs. Further, melanoma patients with mutated CDK13, or less CDK13 in the nucleus, have more aggressive disease, indicating that this is a new high-risk melanoma subset.

These findings have profound implications for cancer therapy. Specifically, targeting the accumulation of aberrant RNAs could provide a new therapeutic avenue, particularly for the 20% of melanoma patients with accumulated aberrant RNA in their tumors.

The Insco lab is dedicated to further exploring the mechanisms of RNA surveillance in melanoma and developing therapeutic strategies for cancers that rely on impaired nuclear RNA surveillance. Their research has identified recurrent mutations in genes encoding nuclear RNA surveillance components across various malignancies, establishing the importance of this pathway in tumor suppression.

The group’s pioneering work in RNA surveillance has uncovered the critical role of RNA quality control in preventing cancer. Their discoveries have opened up new possibilities for therapeutic interventions and have significant implications for understanding and treating melanoma and other cancers associated with disrupted RNA surveillance.

Team Members: Megan Insco, MD, PhD

Applications

Currently, the lab is executing small molecule screens to identify novel modulators of RNA surveillance complexes and to identify lethal targets in melanoma and other tumor types.

The team is using CDK13-mutant melanoma cells as its first model system for identifying compounds capable of destroying them. The Insco lab is also working to uncover small protein sequences with sufficient activity to trigger the degradation of aberrant RNA and kill CDK13-mutant melanoma cells.

The team has also found functional CDK13 mutations in bladder, colorectal, lung, ovarian, and uterine cancers – potentially opening up the possibility of targeting this mutation in these cancer types.

Opportunities

Dana-Farber is interested in partnering with collaborators to identify compounds for therapeutic targeting of the RNA surveillance system.

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