Abstract Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered proteins/protein regions (IDPs/IDRs) driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. The detailed analysis of these IDRs revealed that they can function in multiple ways that are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks independently of the modulation of globular proteins. Disordered drivers are also highly relevant at the sample level, and their mutations can represent the key driving event in certain individual cancer patients. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

How mutations of intrinsically disordered protein regions can drive cancer