Small molecule targeting of R-Ras, a neglected member of the Ras GTPase subfamily, as a novel Wnt pathway component and cancer driver

Development of targeted anti-TNBC (triple-negative breast cancer) therapies will bring hope for millions of patients worldwide. The oncogenic Wnt signaling pathway is the key target to develop the missing therapies, but no Wnt pathway inhibitors currently exist on the market. Translational research performed by our team has led to identification of an innovative, effective and safe small-molecule scaffold targeting the Wnt pathway in TNBC. Our FSA compounds: 1. Inhibit growth and other oncogenic properties of TNBC cell lines in vitro. 2. Reduce growth and inhibit Wnt signaling in three TNBC mouse xenograft models in vivo, including a TNBC cancer stem cell model and a patient-derived xenograft. 3. Do not display overt toxicity and, unlike competitor compounds, lack on-target side effects in the intestine, bone, and hematopoietic system. 4. Through target deconvolution and validation experiments identified to act on a novel and unexpected target – R-Ras, the neglected member of the Ras subfamily of small GTPases. The current project aims at identifying the mode of action of FSA compounds on R-Ras using biochemical, biophysical, and cell biological techniques, and at resolving the structure of R-Ras in complex with the compounds. This structural elucidation will permit rational design of new FSA analogs with improved potency and selectivity, laying the ground for future industrial developments of a first-in-class small molecule anti-Wnt and anti-cancer drug candidate.

Hamad Bin Khalifa University (HBKU)