Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

药物耐受性是对包括奥希替尼在内的表皮生长因子受体 - 酪氨酸激酶抑制剂（EGFR - TKIs）获得性耐药的基础，其机制仍不清楚。在此，我们表明，虽然低AXL表达的表皮生长因子受体突变肺癌（EGFRmut - LC）细胞比高AXL表达的EGFRmut - LC细胞对奥希替尼更敏感，但有一小部分细胞会产生奥希替尼耐受性。这种耐受性是由胰岛素样生长因子 - 1受体（IGF - 1R）的表达增加和磷酸化所介导的，这是由其转录因子FOXA1的诱导引起的。在奥希替尼存在的情况下，IGF - 1R与EGFR以及衔接蛋白（包括Gab1和IRS1）保持关联，并恢复生存信号。在低AXL表达的EGFRmut - LC细胞衍生的异种移植模型和患者来源的异种移植模型中，短暂抑制IGF - 1R并结合持续的奥希替尼治疗可以根除肿瘤，并且即使在停止使用奥希替尼后也能防止肿瘤复发。这些结果表明，对耐受性信号的优化抑制结合奥希替尼可能会显著改善EGFRmut - LC的治疗结果。