RRC ID 75789
Author Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, Dagogo-Jack I, Gadgeel S, Schultz K, Singh M, Chin E, Parks M, Lee D, DiCecca RH, Lockerman E, Huynh T, Logan J, Ritterhouse LL, Le LP, Muniappan A, Digumarthy S, Channick C, Keyes C, Getz G, Dias-Santagata D, Heist RS, Lennerz J, Sequist LV, Benes CH, Iafrate AJ, Mino-Kenudson M, Engelman JA, Shaw AT.
Title Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.
Journal Cancer Discov
Abstract UNLABELLED: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, ALKG1202R, 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.
SIGNIFICANCE:Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.
Volume 6(10)
Pages 1118-1133
Published 2016-10-1
DOI 10.1158/2159-8290.CD-16-0596
PII 2159-8290.CD-16-0596
PMID 27432227
PMC PMC5050111
MeSH Aminopyridines Anaplastic Lymphoma Kinase Carcinoma, Non-Small-Cell Lung / genetics* Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Drug Resistance, Neoplasm* / drug effects Humans Lactams Lactams, Macrocyclic / pharmacology* Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Mutation Protein Kinase Inhibitors / pharmacology Pyrazoles Pyrimidines / pharmacology Receptor Protein-Tyrosine Kinases / genetics* Sulfones / pharmacology
IF 29.497
Human and Animal Cells Ba/F3(RCB0805)