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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