Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.
Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.
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DOI：
10.1158/1535-7163.mct-21-0344
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发表时间：
2022-03
影响因子：
5.7
通讯作者：
Jänne PA
中科院分区：
文献类型：
--
作者：
Bahcall M;Paweletz CP;Kuang Y;Taus LJ;Sim T;Kim ND;Dholakia KH;Lau CJ;Gokhale PC;Chopade PR;Hong F;Wei Z;Köhler J;Kirschmeier PT;Guo J;Guo S;Wang S;Jänne PA
MET靶向治疗MET扩增和MET外显子14缺失突变(METEX 14)的非小细胞肺癌(NSCLC)临床有效，但其疗效受到耐药性发展的限制。结构上不同的MET酪氨酸激酶抑制剂(TKI)(I/II型)已经被开发出来或正在进行临床评估，它们可能会克服MET介导的耐药机制。在这项研究中，我们使用TPR-MET转化的BA/F3细胞突变试验评估了单一药物或I型/II型MET TKI组合治疗后可能出现的继发性MET突变。我们发现，这些抑制剂导致了不同的次生MET突变谱。然而，I型/II型TKI抑制剂(卡马替尼和美司替尼)的组合在体外没有产生耐药克隆。卡马替尼/美司替尼的组合在体内进行了评估，与单独使用MET抑制剂相比，可以显著减少肿瘤的生长。我们的研究结果表明，在体外和体内，同时使用I型和II型MET TKI治疗可能是一种临床上可行的方法，可以延迟和/或减少靶向MET介导的耐药突变的出现。
MET targeted therapies are clinically effective in MET amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLC) but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro. The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared to either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET mediated drug resistance mutations.