Department of Oncology, University of Torino, Candiolo, Italy
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
EMBO Mol Med. 2018 Sep;10(9). doi: 10.15252/emmm.201708746.
The onset of secondary resistance represents a major limitation to long-term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is the key to the rational design of therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-Seq in MET-addicted cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, epigenetically induced miR-205 expression determined the downregulation of ERRFI1 which, in turn, caused EGFR activation, sustaining resistance to MET-TKIs. Anti-miR-205 transduction reverted crizotinib resistance while miR-205 over-expression rendered wt cells refractory to TKI treatment. Importantly, in the absence of EGFR genetic alterations, miR-205/ERRFI1-driven EGFR activation rendered MET-TKI-resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this new mechanism of adaptive resistance, we report that a patient with a -amplified lung adenocarcinoma displayed deregulation of the miR-205/ERRFI1 axis in concomitance with onset of clinical resistance to anti-MET therapy.
继发耐药的出现是癌症患者靶向治疗长期疗效的主要限制因素。因此，确定介导继发耐药的机制是为耐药患者设计合理治疗策略的关键。在依赖 MET 的癌细胞系中，通过 miRNA 图谱分析结合 RNA-Seq，我们发现 miR-205/ERRFI1（表皮生长因子受体反馈抑制剂 1）轴是一种新型的 MET 酪氨酸激酶抑制剂（TKI）耐药的介导体。在对 MET-TKI 耐药的细胞中，表观遗传诱导的 miR-205 表达决定了 ERRFI1 的下调，进而导致 EGFR 激活，维持对 MET-TKI 的耐药性。抗 miR-205 转导可逆转克唑替尼耐药，而 miR-205 过表达使 wt 细胞对 TKI 治疗产生抗性。重要的是，在没有 EGFR 遗传改变的情况下，miR-205/ERRFI1 驱动的 EGFR 激活使 MET-TKI 耐药细胞对 MET/EGFR 联合抑制敏感。作为这一新的适应性耐药机制的临床相关性的概念验证，我们报告了一名 -扩增肺腺癌患者在对抗-MET 治疗出现临床耐药时，出现了 miR-205/ERRFI1 轴失调。
