| 著者 |
Shiba-Ishii A, Johnson TW, Dagogo-Jack I, Mino-Kenudson M, Johnson TR, Wei P, Weinrich SL, McTigue MA, Walcott MA, Nguyen-Phuong L, Dionne K, Acker A, Kiedrowski LA, Do A, Peterson JL, Barth JL, Yeap BY, Gainor JF, Lin JJ, Yoda S, Hata AN.
|
| Abstract |
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.
|
