A bacterial toxin that cleaves Ras: a translational study to provide insights into breast cancer biology and treatment

About 1/3 of all human cancers are driven by mutations in the Rat sarcoma (RAS) genes. When RAS genes are mutated or Ras signaling is hyperactivated, cells grow uncontrollably and evade death signals leading to cancer cell survival, tumor growth and invasive cell behavior. Although only approximately 2% of breast cancers carry a RAS mutation, high Ras activity has been detected in about 50% of breast cancer cell lines and tumor specimens. Despite intensive exploration in the academic and private sector, no effective therapy that targets Ras or hyperactive Ras currently exists and Ras is still considered as a virtually undruggable target for therapy. We discovered that the Ras-Rap1-specific protease or RRSP from bacterium Vibrio vulnificus has specific proteolytic activity against Ras and Rap1 small GTPases, thus inhibiting proliferation of Ras-dependent and Ras-independent cancer cell lines. Here we propose to test the efficacy of RRSP in an in vivo xenograft mouse model of triplenegative breast cancer. Our ultimate goal is to advance the development of effective therapeutics for what is considered one of the most undruggable targets in cancer research and provide proof-of-principle pre-clinical evidence that RRSP can block triple-negative breast cancer tumor growth.