MET Y1230H 有关的猜想 （不构成任何建议）

克唑替尼耐药不仅仅有1228 或1230, 而且可能混杂1200 1195等位置突变，这些突变对二型METTKI是不利的，因此上280克服这些1200 1195 突变后，再上二型会更好。
不过1228N对二型敏感度还是不行。


A unique finding for MET mutation-mediated resistance is that the D1228 and Y1230 resistance mutations are located in the A-loop in contrast to the gatekeeper, solvent front, and binding site mutations implicated in resistance to other tyrosine kinase inhibitors (38). The molecular basis of resistance of these unique A-loop mutations is evident from crystal structures of type I inhibitors such as crizotinib and capmatinib but not type II inhibitors including glesatinib, which bind independently of A-loop interactions. Moreover, molecular modeling of glesatinib bound to MET and the ability to adopt two distinct binding modes provides a molecular explanation as to why glesatinib retains activity against mutations within the A-loop and why the onset of resistance to glesatinib was delayed compared with type I MET inhibitors. Interestingly, the MET L1195V and F1200L/I mutations that were associated with resistance to both inhibitor classes in MET-mutant variant enzyme screens and/or resistance studies occur distal from the ligand binding site of type I inhibitors and may result in enhanced substrate affinity or destabilization of the autoinhibited A-loop conformation. Consistent with the observed resistance, biochemical screens in the current studies indicated a 10-fold loss of activity for crizotinib for MET F1200I compared with WT and this was the same amino acid that was found mutated in a crizotinib drug resistance screen (39). Although the MET F1200I mutation did not emerge as an acquired resistance mechanism during glesatinib drug resistance screens, there is direct involvement of this residue in the type II DFG-out binding mode, which would provide a clear molecular basis for attenuated activity for glesatinib and other type II inhibitors and is consistent with the 4-fold decrease in potency in crizotinib-resistant cells that harbored the Y1230H/F1200L double mutation. Interestingly, the type Ib inhibitor, savolitinib, demonstrated potent inhibitory activity against the F1200I variant suggesting it has a binding mode distinct from other type Ib MET inhibitors and supports the utility of this agent as another potential option to combat mutation mediated resistance via sequential treatment strategies. The relatively modest loss of glesatinib activity against the L1195V and F1200L mutations relative to most other type I inhibitors suggests that glesatinib may not rely solely on a single binding mode and may be able to adopt a conformation that attenuates loss of activity. Glesatinib was also evaluated against a panel of twelve other known MET mutations and activity was comparable with WT MET; thus, no additional anticipated glesatinib resistance mutations have been identified (partial data summary in Supplementary Table S2).

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glesatinib 是唯一一种不带抗血管生成作用的2型METTKI。文章中提示卡博和梅沙都有抗VEGF作用。

Collectively, the current studies further the understanding and support the clinical relevance of METex14 del mutations as an oncogenic driver class in NSCLC. In addition, these studies indicate that although targeting MET driver mutations with selective inhibitors has the potential to be an effective therapeutic strategy, this strategy will also be subject to drug resistance like other targeted therapies. MET active site mutations, particularly A-loop mutations, are predicted to be an important mechanism of resistance based on these and other emerging data as well as structure-based modeling of the MET active site. Glesatinib and other type II inhibitors appear to be positioned to address resistance mediated by these mutations. Although other type II inhibitors that target MET such as cabozantinib and merestinib have been reported, glesatinib is the only type II MET inhibitor that spares VEGF receptors at clinically achievable drug concentrations indicating it may be uniquely positioned to address resistance while avoiding well-known dose-limiting toxicities associated with VEGFR inhibition. Another important observation is that type I and type II inhibitors may have utility in sequential therapeutic strategies if orthogonal resistance mechanisms emerge for each inhibitor mode. Together, these studies demonstrate that glesatinib exhibits a differentiated mechanism of target inhibition, is active against METex14 del–mutant lung cancer, including tumors exhibiting certain acquired resistance to other MET inhibitor classes, and glesatinib may represent a therapeutic option for these cancers.

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F1200L和Y1230H同时存在的问题。

The 4-fold shift in potency in cell viability assays observed for glesatinib in the crizotinib-resistant but not capmatinib-resistant line also suggests that the presence of the F1200L variant in cis with Y1230H may impact the activity of both crizotinib and glesatinib.

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https://aacrjournals.org/clincancerres/article/23/21/6661/259173/Glesatinib-Exhibits-Antitumor-Activity-in-Lung  
二型glesatinib对MET耐药的作用。

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下面的实验再次证明 D1228N比Y1230C对二型MET抑制剂更不敏感。
另外单独MET 1230C点突变比 1230C+MET14跳 对二型更敏感。
是不是意味着应该后者应该1型+二型对付。

We next evaluated crizotinib, capmatinib, and glesatinib in NIH/3T3 cell line–derived tumor xenograft models engineered to express MET Y1230C, the METex14 del Y1230C double mutant, or the METex14 del D1228N double mutant implanted into the hind flank of immunocompromised SCID mice expressing the human HGF transgene. Because these MET variants are dependent on HGF binding for complete activation and as mouse HGF binds human MET with low affinity (33), the hHGFtg-SCID model was utilized to evaluate the activity of MET inhibitors in models exhibiting MET mutation variants (34, 35). Treatment of established tumors with crizotinib (50 mg/kg) or capmatinib (30 mg/kg, twice daily) at previously reported dose regimens did not appreciably inhibit tumor growth (Fig. 5F–H). In contrast, daily administration of glesatinib (60 mg/kg) resulted in tumor regression of the MET Y1230C (maximum regression of 88% on day 13), METex14 del Y1230C (maximum regression of 52% on day 13), and METex14 del D1228N (maximum regression of 21% on day 3) xenografts. In general, the antitumor activity of glesatinib was comparable with the activity seen in METex14 del mutant and amplified cell line and PDX models; however, the growth of some METex14 del D1228N tumors began to recover after the initial regression suggesting that this double mutation is not as sensitive to glesatinib as the METex14 del Y1230C double mutation.

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今天赵军抖音说TP53 5号和8号外显子突变的容易耐药

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这几天大家都在讨论免疫，对于MET 有靶向药的一定靶向药为先，后期无药可医可以试试免疫，不过最好是在身体状况好的时候。
免疫的副作用有时候不一定比安罗 184 厉害。

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　卡马替尼该药物具有口服生物利用度，主要由CYP3A4和醛氧化酶代谢。

                               
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469625785 发表于 2022-05-22 00:08
恩沙不是ALK的药吗？

最新的国内实验发布，对MET 你可以看看，基本属于1型。入脑不错，副作用和其他MET药有差异。

https://mp.weixin.qq.com/s/YPkUYtL0L_dg-k5Aq-_1PQ

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吕超 发表于 2022-05-21 22:19
恩沙替尼还有一个特点，就是皮疹发生率比较高。而这个皮疹与EGFR-TKI导致的皮疹完全不一样，有点像培美曲赛引发的皮疹，就是所谓的丘疹，而且这种丘疹通常情况下它的处理就是使用类固醇激素，特别是使用外涂软膏处理疗效就非常好，也非常简单。所以我认为如果能够做好恩沙替尼的副作用处理，那么它在一线治疗使用的潜力是非常大的。因为恩沙替尼的肝毒性非常小，这一点上与阿来替尼有一定区别。

恩沙替尼对脑转移人群的有效率超过60%，而在预防脑转移方面，我们在恩沙替尼全球三期临床研究中观察到，恩沙替尼一线治疗12个月时，脑转移的发生率为4%左右。也就是说，无论是脑转移控制能力，还是预防脑转移发生，这两者恩沙替尼均明显好于克唑替尼。

论坛已经开始讨论 卡马水肿厉害，交替恩沙的方案。

恩沙不是ALK的药吗？

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