Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

• DOI: 10.1038/s43018-022-00399-6
• Publication Date: 2022-06-20T16:07:21Z
• Authors: Aya Shiba-Ishii; Ted W. Johnson; Ibiayi Dagogo-Jack; Mari Mino-Kenudson; Theodore R. Johnson; Ping Wei; Scott L. Weinrich; Michele A. McTigue; Makeba A. Walcott; Linh Nguyen-Phuong; Kristin Dionne; Adam Acker; Lesli A. Kiedrowski; Andrew Do; Jennifer L. Peterson; Jaimie L. Barth; Beow Y. Yeap; Justin F. Gainor; Jessica J. Lin; Satoshi Yoda; Aaron N. Hata
• Keywords: ALK inhibitor; Acquired resistance; Targeted Therapy

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.