The research carried out by Matthew J. Smith and his team aims to integrate modern experimental approaches in structural biology, biophysics, evolutionary bioinformatics and cell biology to help identify and understand both normal and disrupted cell signalling at a mechanistic and systems level.
Cancers are driven by anomalous changes to the genetic material of various cell types. These changes frequently result in the creation of mutated proteins, or an overproduction of proteins, leading to unregulated cell growth. Matthew Smith and his team study the relationship between structure and function for numerous proteins crucial to both normal and oncogenic cell signalling pathways.
They explore how genetic mutations correlate with altered protein function, how this might disrupt signalling networks, and ultimately how genetic aberrations truly trigger cell transformation and/or metastasis. This research provides both fundamental scientific understanding of proteins and cells, and ultimately detailed knowledge that will serve as a basis for developing the next generation of targeted therapies.
The RAS GTPase proteins have long been identified as key drivers of the most refractory human cancers, with a remarkable 30% of tumours harbouring RAS mutations. Despite monumental effort, there are no clinically available drugs targeting the RAS proteins themselves. Instead, several therapies targeting the direct “effectors” of RAS, including RAF and PI3K, are now in clinical use but have proven ineffective due to acquired resistance mechanisms in patients.
It is thus evident that a better understanding of RAS-associated signalling pathways and the proteins that mediate phenotypic responses downstream of RAS are required to advance clinical outcomes. To that end, Matthew Smith’s team works to integrate approaches in genomics, targeted structural biology, cellular signaling, and proteomics to better understand how central, highly plastic RAS signaling networks function to initiate and drive transformation. These detailed analyses of RAS network interactions with other biomolecules will pave the way for improvements in drug design and therapeutic approaches that will define the next generation of cancer treatments.