Truncated ErbB2 Expressed in Tumor Cell Nuclei Contributes to Acquired Therapeutic Resistance to ErbB2 Kinase Inhibitors

Abstract

ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185ErbB2). In addition to p185ErbB2 truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously demonstrated. Here we show that expression of a 95 kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2+ breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2+ breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated c-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib sensitive ErbB2+ breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation, may enhance the clinical efficacy of ErbB2 TKIs.

Photo-Activated Psoralen Binds the ErbB2 Catalytic Kinase Domain, Blocking ErbB2 Signaling and Triggering Tumor Cell Apoptosis

“…We have also shown that expression of an 85 kDa truncated form of ErbB2 (p85 ErbB2 ) that lacks the extracellular and transmembrane domains, is preferentially expressed in the nuclei of tumors that have become resistant to lapatinib [17]. Moreover, expression of p85 ErbB2 under the control of a heterologous promoter can render cells resistant to lapatinib and other ErbB2 targeted drugs in otherwise sensitive ErbB2+ breast cancer cells [17].…”

“…Moreover, expression of p85 ErbB2 under the control of a heterologous promoter can render cells resistant to lapatinib and other ErbB2 targeted drugs in otherwise sensitive ErbB2+ breast cancer cells [17]. Although p85 ErbB2 is tyrosine phosphorylation, an indication of its activated state, it is not inhibited by lapatinib (Figure 7) [17].…”

Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications

“…35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib. 36 The frequency and clinical significance of this finding are unknown at this time.…”

Receptor Tyrosine Kinases in the Nucleus

“…The CTFs, which are generated at three methionine residues located on either side of the transmembrane domain, are found in the nucleus (Anido et al 2006;Xia et al 2011). These fragments promote cell migration ) and are reported to be oncogenic ).…”