Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers

• Published in: Science translational medicine Vol. 4; no. 120; p. 120ra17
• Main Authors: Katayama, Ryohei, Shaw, Alice T, Khan, Tahsin M, Mino-Kenudson, Mari, Solomon, Benjamin J, Halmos, Balazs, Jessop, Nicholas A, Wain, John C, Yeo, Alan Tien, Benes, Cyril, Drew, Lisa, Saeh, Jamal Carlos, Crosby, Katherine, Sequist, Lecia V, Iafrate, A John, Engelman, Jeffrey A
• Format: Journal Article
• Language: English
• Published: United States 08-02-2012
• Subjects: Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Humans; Immunoblotting; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Mutation; Polymerase Chain Reaction; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3003316

Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.