Elucidating the Role of Truncated ErB2 Receptor (p95) in Breast Cancer

摘要

Our research has elucidated a novel mechanism of therapeutic resistant to ErbB2 tyrosine kinase inhibitors (TKI) mediated by truncated, activated forms of ErbB2 that are expressed in the nuclei of ErbB2+ breast cancer cells. ErbB2 TKI (e.g. lapatinib) induce the expression of a truncated form of ErbB2 that we refer to as p95L, which is expressed in a tyrosine phosphorylated state in the nuclei of ErbB2+ breast cancer cells, where it is resistant to inhibition by ErbB2 TKI. Induction of p95L is proteasome-dependent, and is blocked by proteasome inhibitors, the latter representing a potential therapeutic strategy to inhibit p95L expression and potentially overcome resistance. Similar to p95L, c-611 is a truncated form of ErbB2 generated by alternate initiation of translation, which is expressed in tumor cell nuclei in a phosphorylated state, resistant to ErbB2 TKI. Importantly, expression of c- 676 in the nuclei of ErbB2+ breast cancer cells that are normally sensitive to lapatinib-induced apoptosis, rendered cells resistant to ErbB2 TKI. Studies to determine the function of nuclear truncated forms of ErbB2 are underway.