ROS1 CD74-ROS1 L2026M

L2026M突变被认为是位于ROS1抑制剂结合囊中的一种门控突变，与ALK中的L1196M和EGFR中的T790M相对应。据报道，这种突变在一名患者身上没有观察到，但被推断为一种可能出现在抗克里佐替尼肿瘤中的变异。体外激酶活性、结构预测和生长抑制试验表明，CD74-ROS1融合中的L2026M突变提供了环唑替尼耐药性。其他临床前分析表明，含有这种突变的环唑天宁耐药细胞对PF-06463922和Foretinib敏感。
The L2026M mutation is considered a gatekeeper mutation located in the inhibitor binding pocket of ROS1 and corresponding to L1196M in ALK and T790M in EGFR. This mutation has not been reportedly observed in a patient but inferred as a variant likely to emerge in crizotinib-resistant tumors. In vitro kinase activity, structural predictions and growth inhibition assays indicate the L2026M mutation in the CD74-ROS1 fusion provides crizotinib resistance. Additional preclinical assays have indicated that crizotinib resistant cells harboring this mutation are sensitive to PF-06463922 and foretinib.