Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound.

中文翻译：

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通过 mTOR 和自噬抑制靶向慢性粒细胞白血病中不依赖于 BCR-ABL 的 TKI 耐药性


伊马替尼和第二代酪氨酸激酶抑制剂（TKI）尼罗替尼和达沙替尼在统计学上显着改善了慢性粒细胞白血病（CML）患者的预期寿命；然而，对 TKI 的耐药性仍然是一个重大的临床挑战。尽管第三代 TKI 普纳替尼可改善具有 BCR-ABL 依赖性耐药机制（包括 T315I 突变）的患者的预后，但仍有一部分患者可能患有或发展出不依赖于 BCR-ABL 的耐药性，从而使普纳替尼治疗失败。通过对 ponatinib 耐药性进行建模并测试这些 CML 患者的样本，希望能够识别出替代药物靶标并用新型化合物进行抑制。