Intrinsically disordered protein mutations can drive cancer and their targeted interference extends therapeutic options

Intrinsically disordered regions (IDRs) are important functional modules of several proteins, providing extra layers of regulation as switchable structural elements. Protein disorder has been associated with cancer, but it is unknown whether IDR mutations represent a distinct class of driver events associated with specific molecular mechanisms and system level properties, which would require dedicated targeting strategies. Based on an integrative computational approach, we identified 47 IDRs whose genetic mutations can be directly linked to cancer development. While not as common as alterations of globular domains, IDR mutations contribute to the emergence of the same cancer hallmarks through the modulation of distinct molecular mechanisms, increased interaction potential and specific functional repertoire. We demonstrate that in specific cancer subtypes, IDR mutations represent the key events driving tumorigenesis. However, treatment options for such patients are currently severely limited. We suggest targeting strategies that could enable successful therapeutic intervention for this subclass of cancer drivers, extending our options for personalized therapies.