A study on the mechanisms underlying resistance acquisition of lung cancer for tyrosine kinase inhibitors

酪氨酸激酶抑制剂（TKI）对EGFR突变的肺癌有效，但这些肿瘤最终获得耐药性。在本研究中，我们发现一些TKI治疗的肿瘤主要由EGFR野生型肿瘤细胞组成，而EGFR突变型肿瘤细胞消失或明显减少，并且其预治疗的肿瘤含有EGFR野生型肿瘤细胞。此外，对于手术切除的TKI未治疗的病例，我们发现大多数EGFR突变型肿瘤也含有EGFR野生型肿瘤细胞。因此，多种机制强调了获得性TKI耐药，除了报告的继发性EGFR T790 M突变和适应性Met扩增外，预先存在的TKI耐药EGFR野生型肿瘤细胞的选择性存活也有助于药物获得。

Tyrosine kinase inhibitor(TKI) is effective for lung cancers with EGFR mutation, but these tumors eventually acquire drug resistance. In the present study, we found that some TKI-treated tumors mainly composed of EGFR-wild tumor dells while the EGFR-mutant ones vanished or markedly decreased, and their pre-treated tumors contained EGFR-wild tumor cells. Furthermore, with surgically resected TKI-untreated cases, we showed that most EGFR-mutant tumors also contained EGFR-wild tumor cells. Thus, multiple mechanisms underline acquired TKI resistance, and besides the reported secondary EGFR T790M mutation and adaptive Met amplification, the selective survival of the preexisting TKI-resistant EGFR-wild tumor cells also contributes to the drug acquisition.