Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
Pfizer Worldwide Research and Development, La Jolla, CA, USA.
Nat Cancer. 2022 Jun;3(6):710-722. doi: 10.1038/s43018-022-00399-6. Epub 2022 Jun 20.
Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.
洛拉替尼是目前临床上用于治疗 ALK 阳性非小细胞肺癌最先进、最有效和选择性最高的间变性淋巴瘤激酶 (ALK) 酪氨酸激酶抑制剂；然而，不同的复合 ALK 突变会导致治疗耐药性的出现。在这里，我们确定了洛拉替尼耐药性复合 ALK 突变的范围，这些突变发生在患者接受洛拉替尼治疗后，其中大多数涉及 ALK G1202R 或 I1171N/S/T。我们进一步鉴定了结构多样的洛拉替尼类似物，它们对 G1202R 与 I1171N/S/T 复合 ALK 突变具有不同的选择性特征。结构分析表明，通过提高对 G1202R 或 I1171N/S/T 突变激酶的抑制作用，增加了对复合突变的效力。总的来说，我们提出了一种异质 ALK 复合突变的分类方法，为继酪氨酸激酶抑制剂后的精确靶向治疗提供了不同的治疗策略。
