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

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.

• 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
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 6 Pg. 710-722 (06 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35726063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Aminopyridines
• Lactams
• Lactams, Macrocyclic
• Protein Kinase Inhibitors
• Pyrazoles
• Anaplastic Lymphoma Kinase
• lorlatinib

Topics

• Aminopyridines
• Anaplastic Lymphoma Kinase (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Lactams
• Lactams, Macrocyclic (pharmacology)
• Lung Neoplasms (drug therapy)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles