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Hypothesis: Mutations in the kinase domain that provide resistance to Ponatinib are distinct from those that provide resistance to Dovitinib and may show that Ponatinib is more effective as a first line therapy.
Our laboratory identified mutations in FGFR2 in endometrial cancer (EC) (Pollock et al 2007) and has showed that inhibition of FGFRs induces cell death. Kinase inhibitors have been associated with remarkable clinical responses, however patients often develop resistance mutations in the kinase domain, which prevents drug binding and the cancer returns.
Our lab generated preclinical data that patients with mutations affecting the N550 codon, occurring in 25%, of EC patients will show intrinsic resistance to Dovitinib but should be more sensitive to Ponatinib. Within a large collaboration, our lab is initialling a clinical trial to test the efficacy of the multi-kinase inhibitor Ponatinib (Ariad), in EC patients. The aim of this project is to perform a functional BaF3 mutation screen to identify mutations in FGFR2 that provide acquired resistance to commercially available Ponatinib. These mutations will then be mapped on to the existing crystal structures of the FGFR2 kinase domain to determine the molecular mechanism underlying htem, which will assist in the design of second line therapies.