Crizotinib-Induced Abnormal Signal Processing in the Retina.
Molecular target therapy for cancer is characterized by unique adverse effects that are not usually observed with cytotoxic chemotherapy. For example, the anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor crizotinib causes characteristic visual disturbances, whereas such effects are rare when another ALK-tyrosine kinase inhibitor, alectinib, is used. To elucidate the mechanism responsible for these visual disturbances, the responses to light exhibited by retinal ganglion cells treated with these agents were evaluated using a C57BL6 mouse ex vivo model. Both crizotinib and alectinib changed the firing rate of ON and OFF type retinal ganglion cells. However, the ratio of alectinib-affected cells (15.7%) was significantly lower than that of crizotinib-affected cells (38.6%). Furthermore, these drugs changed the response properties to light stimuli of retinal ganglion cells in some of the affected cells, i.e., OFF cells responded to both ON and OFF stimuli, etc. Finally, the expressions of ALK (a target receptor of both crizotinib and alectinib) and of MET and ROS1 (additional target receptors of crizotinib) were observed at the mRNA level in the retina. Our findings suggest that these drugs might target retinal ganglion cells and that the potency of the drug actions on the light responses of retinal ganglion cells might be responsible for the difference in the frequencies of visual disturbances observed between patients treated with crizotinib and those treated with alectinib. The present experimental system might be useful for screening new molecular target agents prior to their use in clinical trials.
Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Toshiyuki
T
Ishii
Department of Medical Oncology, Graduate School of Medicine, Chiba University1-8-1, Inohana Chuo-ku, Chiba 260-8670, Japan.
Shunichiro
S
Iwasawa
Department of Medical Oncology, Graduate School of Medicine, Chiba University1-8-1, Inohana Chuo-ku, Chiba 260-8670, Japan.
Ryota
R
Kurimoto
Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; Tokyo Medical Care and Welfare Vocational School, 1-11-11 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan.
Akemi
A
Maeda
Department of Medical Oncology, Graduate School of Medicine, Chiba University1-8-1, Inohana Chuo-ku, Chiba 260-8670, Japan.
Yuichi
Y
Takiguchi
Department of Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Makoto
M
Kaneda
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D000077547:Crizotinib; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism
D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse; C582670:alectinib