Pyrotinib, a novel pan-HER tyrosine kinase inhibitor, has demonstrated substantial anti-tumor activity in non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. However, the inevitable resistance to pyrotinib necessitates an in-depth understanding of the underlying mechanisms. In this study, potential resistance-associated mutations were identified through genomic sequencing of clinically paired samples and were validated using in vitro and in vivo models. The cohort for this study comprised 40 patients with paired baseline and resistance samples. Analysis of novel mutations upon the development of resistance did not identify any predominant secondary HER2 mutations. Nevertheless, 12 secondary HER2 mutations (38.7%) occurred either as single nucleotide variations (SNVs, 75%) or insertions/deletions (Indels, 25%), based on HER2 p.Y772_P775dup mutation. Only two mutations led to HER2 autophosphorylation and IL3-independent proliferation of Ba/F3 cells from the in vitro experiments, implying that the remaining 10 secondary mutations were passenger mutations. Further in vivo and in vitro validation showed that the HER2 p.E770_A771insAYMM mutation significantly diminished the sensitivity of murine HER2 mutant lung adenocarcinoma cell line to pyrotinib, with ineffective inhibition of HER2 and its downstream pathways. Drug screening indicated that mobocertinib and dacomitinib could effectively restrain the growth of tumors bearing the HER2 p.E770_A771insAYMM mutation. In summary, our findings unveil a new form of resistance-a secondary mutation superimposed on the original mutation-and offer insights into a potentially sequential strategy for overcoming resistance to pyrotinib.
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