The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mut..... READ ARTICLE
BioRxiv DOI:10.1101/2021.07.16.452681
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 Kiedrowski, Andrew Do, Jennifer L Peterson, Jaimie L Barth, Beow Y Yeap, Justin F Gainor, Jessica J Lin, Satoshi Yoda, Aaron N Hata