HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors

Abstract

HER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776(YVMA) insertion in exon 20 was more potent than wild-type HER2 in associating with and activating signal transducers, phosphorylating EGFR, and inducing survival, invasiveness, and tumorigenicity. HER2(YVMA) transphosphorylated kinase-dead EGFR(K721R) and EGFR(WT) in the presence of EGFR tyrosine kinase inhibitors (TKIs). Knockdown of mutant HER2 in H1781 lung cancer cells increased apoptosis and restored sensitivity to EGFR TKIs. The HER2 inhibitors lapatinib, trastuzumab, and CI-1033 inhibited growth of H1781 cells and cells expressing exogenous HER2(YVMA). These data suggest that (1) HER2(YVMA) activates cellular substrates more potently than HER2(WT); and (2) cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs.

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…It induced transphosphorylation of kinase‐dead EGFR, and exhibited higher ligand‐independent tyrosine phosphorylation. Moreover, the insertions were more potent than wide‐type HER‐2 in associating with signal transducers that mediate proliferative and prosurvival responses 44.The activating missense mutations in kinase domain have also been reported. Most of the mutations were detected in the αC‐helix which is considered to play a critical role in the activation of HER‐2 gene 23.…”

“…These insertions are more potent in transphosphorylating EGFR compared with the wild‐type HER‐2. Conclusively, the mutant HER‐2 gene is more transforming and more capable to inhibit the effect of apoptosis 44.…”

“…Human epidermal growth factor receptor‐2 gene with some kinase domain mutations shows the characteristics of constitutively activate kinase activity and increased oncogenicity compared to the wild‐type HER‐2 44. The positive effect of activating mutations on tumour growth has been demonstrated in vitro 23.…”

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

“…Previous studies [51] have shown cells harboring HER2 mutations undergoing constitutive phosphorylation and activation of HER2 and show resistance to EGFR TKIs. Treatment with small-molecule tyrosine kinase inhibitors that target the kinase activity of both EGFR and HER2 eg Lapatinib, tested as HKI-272, have been found to be effective.…”

“…They are reported in 2% of NSCLC [50,51]. ERBB2/HER2 mutations involve inframe insertions in exon 20, mostly involving the amino acid sequence Tyr-Val-Met-Ala at codon 776.…”