ERBB2 (or HER2) is an atypical transmembrane receptor tyrosine kinase that does not bind a ligand on its extracellular domain, yet still manages to activate numerous intracellular pathways that regulate cell growth, including MAPK and PI3K. Wild-type (WT) ERBB2 relies on dimerization to activate its intracellular kinase domain, but genetic mutations may constitutively activate kinase activity causing unregulated cell growth and, subsequently, tumorigenesis.
While several drugs have been FDA-approved to inhibit the hyperactivity of overexpressed WT ERBB2 in breast cancer, it is unclear how efficient these treatments will be in patients with oncogenic ERBB2 mutations, though we suspect efficacy will vary greatly depending on the location of the mutation and the nature of the pharmacological agent involved. We aim to characterize these mutations and determine how they affect the activity of ERBB2 through use of soft agar assays using 3T3 cells expressing mutant forms of ERBB2.
Preliminary results indicate that several of the mutants increase the activity of ERBB2 as shown by increased colony formation in soft agar assays. Furthermore, we performed assays to determine the effectiveness of ERBB2 inhibitors in reducing survival of cancer cell lines known to have these ERBB2 mutations and found that drug sensitivity was variable. Further analysis of which therapeutics are effective against these mutants of ERBB2 along with determination of combination therapies based on other genomic features of these cell lines may greatly enhance our ability to treat ERBB2-mutant cancer.
PROJECT: Functional evaluation of ERBB2 mutations in cancer cell lines
Mentors: Heidi Greulich and Bethany Kaplan, Cancer Program
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