Justin F Gainor 1 , Leila Dardaei 1 , Satoshi Yoda 1 , Luc Friboulet 2 , Ignaty Leshchiner 3 , Ryohei Katayama 4 , Ibiayi Dagogo-Jack 1 , Shirish Gadgeel 5 , Katherine Schultz 1 , Manrose Singh 1 , Emily Chin 1 , Melissa Parks 1 , Dana Lee 1 , Richard H DiCecca 1 , Elizabeth Lockerman 1 , Tiffany Huynh 6 , Jennifer Logan 1 , Lauren L Ritterhouse 6 , Long P Le 6 , Ashok Muniappan 7 , Subba Digumarthy 8 , Colleen Channick 1 , Colleen Keyes 1 , Gad Getz 3 , Dora Dias-Santagata 6 , Rebecca S Heist 1 , Jochen Lennerz 6 , Lecia V Sequist 1 , Cyril H Benes 1 , A John Iafrate 6 , Mari Mino-Kenudson 6 , Jeffrey A Engelman 9 , Alice T Shaw 9
Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK(G1202R), increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.