Abstract
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.
Highlights
The development of drugs for targeted therapy has revolutionized cancer therapy
The actions of crizotinib on the firing rate were classified into no change type (Fig 1A), increase type (Fig 1B), and decrease type (Fig 1C)
Among the cells that showed a change in the firing rate, the change in the firing rate occurred soon after the application of crizotinib
Summary
The development of drugs for targeted therapy has revolutionized cancer therapy. Some of these drugs promise significant responses for patients with cancers expressing the molecular target. These drugs have specific and unique adverse effects that differ from those of cytotoxic agents. Skin disorders including rashes, pruritus, and acne are seen in patients treated with gefitinib [1], erlotinib [2] and cetuximab [3], while severe diarrhea is seen in patients treated with afatinib [4].
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