MET Y1230H 有关的猜想 （不构成任何建议）

吕超 发表于 2022-04-09 05:39
INC280：随餐吃，血药浓度增加 30%。（这个说法有待证实）
大家目前所用剂量偏低，原标准是空腹，因此可改为随 餐，改善效果和耐受性。

诺华在其 2017 年的一份专利中指出，INC280 联合特罗凯，IN280 可以吃 8 天停 2 天。 280 可以吃 8 停 2 是为什么呢，280 的半衰期不是只有 4 个小时左右吗？ 老马：因为药厂发现 280 连续服用会导致老鼠体重降低。而且是在第 9 天出现，然后试验停药 2-3 天，发现体重恢复正常。

我目前采用的的方案是吃7停1 ，随餐吃. 不太敢吃8停2

吃7停1？请问这样是可以延缓耐药么？

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https://www.sciencedirect.com/topics/medicine-and-dentistry/merestinib
梅沙替尼的确有轮回280的希望，但是在啥条件下，值得思考和研究。
有时候梅沙可能就是一个桥梁或者清除机，不在乎长短，在乎能否回到一型。

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280+曲美 也是对抗耐药的一种尝试。
曲美的副作用是皮疹 抵抗MET耐药1-2个月还是有些希望，不能抱有长久希望。

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天津肿瘤医院肌酐超过10%就不给做增强核磁了
增强CT 增强核磁 打的药对肾功有影响

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所谓MET14跳突不和其他突变主驱动共存也是不对的。KRAS和MET14并存，克和280竟然无效。
其实真的挺复杂。一山不容二虎，谁是主驱动，真的很复杂。
KRAS是MET继发的耐药机制，但是以前感觉原发存在的并不是MET14的耐药机制。
但是KRAS可能太强了，直接驱动，或者双驱动，即使阻止了MET14也没用。

                               
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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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