Cancer Signaling and Structural Biology

Figure6Cancers 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. The protein RAS has long been recognized as a key driver of human cancers with fully 30% of tumours having RAS mutations, making it a major target for drug development. RAS proteins are encoded by three proto-oncogenes: HRAS, KRAS and NRAS. Of these, KRAS mutations are most frequent in human cancers, present in 22% of all tumours and 61% of pancreatic, 33% of colon and 17% of lung cancers. These are amongst the most clinically refractory cancers we have today, with lung carcinomas representing the leading cause of cancer death world-wide.

Despite extensive efforts, there are no clinically successful drugs that target RAS itself. Rather, advancements in treating RAS-driven cancers have come via targeting downstream effector pathways or upstream receptors. Unfortunately, these targeted treatments do not always translate into significant clinical progress due to the most pressing obstacle in cancer therapy today: the prevalence of acquired drug resistance. It has become evident that combination therapies targeting multiple RAS-associated pathways and multiple levels within these pathways will be necessary to advance clinical outcomes for patients with RAS-driven tumours.

To achieve this, our group is developing novel therapeutic strategies by integrating approaches in genomics, targeted structural biology, advanced cellular signaling assays, and proteomics to better understand how central, highly plastic RAS signaling networks function to initiate and drive transformation. This includes identification of new signaling partners, structural and biophysical characterization of key protein interactions, and cell biology approaches to assess novel biochemical observations. These detailed analyses of RAS network interactions with biomolecules will pave the way for improvements in drug design and therapeutic approaches that will define the next generation of anti-cancer treatments.

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