Somatic kRAS mutations, termed oncogenic kRas, are found at a high rate in many cancers. For example, in colon cancer, the rate is 40%. Mutated KRAS allows the EGF system to bypass its natural controls and operate continuously, locked in a pro-growth mode (wild-type kRas, but not oncogenic KRAS, is self- inactivating). Consistent with this mechanism, the presence of mutated KRas predicts lack of response to anti- EGF monoclonal antibody therapeutics such as panitumumab (Vectibix) and cetuximab (Erbitux) in colorectal cancer. The goal of this grant is to discover compounds that specifically inhibit oncogenic kRas without affecting normal kRAS. Such molecules would be expected to restore the anti-cancer efficacy of anti-EGF therapeutics such as panitumumab and cetuximab when administered to patients with oncogenic kRas. Unfortunately, many previous efforts to target oncogenic KRas have failed, and kRAS has been declared an """"""""intractable"""""""" target by many cancer researchers. However, we recently developed a unique screening model using a genetically modified D. melanogaster that expresses mutant, oncogenic kRAS (G12V) in their wings while maintaining normal kRAS in the rest of their bodies. We plan to use this fly as a screening platform to search for drugs that inhibit mutant kRAS while not affecting wild-type kRAS. The phenotype for the mutated fly is a """"""""crimped"""""""" wing, and a """"""""hit"""""""" in the assay would be a compound that prevents formation of the crimped wing defect. The use of the fly permits screening in a whole animal, which is expected to produce more reliable """"""""hits"""""""" than screening in cell culture or in biochemical assays. In addition, the whole animal model permits a preliminary evaluation of safety, because only compounds that permit development of normal, healthy flies while blocking the mutant kRAS in their wings will be selected as """"""""hits"""""""". Compounds toxic in flies will not pass the screen. Activities to be funded by the grant include further characterizing the transgenic fly and the assay, establishing an assay to differentiate inhibitors of oncogenic and wild-type kRAS, screening for potential inhibitors, structural optimization of """"""""hits"""""""", and characterization of optimized """"""""hits"""""""" in PK, safety and kRAS-relevant xenograft studies.
The goal of this grant is to discover chemicals that specifically inhibit oncogenic kRAS without affecting normal kRAS. When administered to patients receiving anti-EGF therapy, such molecules would be expected to restore the anti-cancer efficacy of anti-EGF therapeutics such as panitumumab (Vectibix(R)) and cetuximab (Erbitux(R)) which has been diminished by the expression of oncogenic kRAS.
