Functional analysis of somatic mutation in cancer.
We are interested in identification of novel oncogenes and therapeutic targets from somatic mutation data generated by large-scale cancer genome sequencing experiments. For example, we recently identified novel recurring mutations of the extracellular domain of the receptor tyrosine kinase gene ERBB2 in lung, breast, and bladder cancer. The extracellular domain mutations of ERBB2 are oncogenic, and a subset of these mutations activates the receptor by covalent dimerization mediated by intermolecular disulfide bonds. Although the extracellular domain ERBB2 mutants are sensitive to existing ERBB2 inhibitors in isogenic engineered systems, response is more variable in the complex genomic setting of an actual tumor cell. Our current focus is understanding the genomic features of ERBB2-mutant tumor cells that predict senstivity to ERBB2 inhibitors.
