Abstract
ALK rearrangement-positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown. By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied. Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK-expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity. Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK-driven tumors.
Highlights
ALK gene fusions occur in 2% to 7% of lung adenocarcinomas [1, 2]
Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic
EML4-ALK variants v1 and v3b showed no significant differences in the half-maximal growth inhibitory concentration ("GI50 values") when treated with the aminopyridine ALK inhibitor crizotinib (PF02341066; GI50 values 470 nmol/L, Fig. 1A)
Summary
ALK gene fusions occur in 2% to 7% of lung adenocarcinomas [1, 2]. These fusions are oncogenic in vitro and in vivo and cause oncogene dependency by constitutive kinase activation of the ALK tyrosine kinase [1, 3]. A phase I/II study in advanced, ALK-positive, Authors' Affiliations: 1Department of Translational Genomics, 2Department I of Internal Medicine and Center of Integrated Oncology Ko€ln–Bonn, 3Institute of Pathology, University of Cologne; 4Max Planck Institute for Neurological Research; 5Department of Hematology and Oncology, Vanderbilt University School of Medicine Nashville, Tennessee; and 6Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
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