Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2.
Bottom Line: In addition, S-222611 showed potent antitumor activity over lapatinib in a variety of xenograft models.In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis.Considering the safer profile than for irreversible inhibitors, S-222611 could be an important option in future cancer therapy.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.Show MeSH
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Mentions: Recently, several irreversible EGFR/HER2 inhibitors have been evaluated in clinical trials and shown promising efficacy.(9)– (15) We compared the antitumor activity of S-222611 with irreversible inhibitors neratinib and afatinib (Fig. 4a). If we simply compared these drugs at the same dose, the efficacy of S-2322611 was weaker than those of both irreversible inhibitors, although statistical significance was observed only between 25 mg/kg S-222611 and 25 mg/kg afatinib. Generally, irreversible inhibitors are more potent in kinase inhibition and antitumor activity than reversible inhibitors, but the clinical trials of these irreversible inhibitors revealed that the frequency and degree of the adverse effect are also significantly increased.(10)– (15,32,33) To assess the toxicity profile, we conducted a histopathological examination with mice used in the antitumor efficacy studies and observed the pivotal toxicity in the colon and eyeball in neratinib-treated and afatinib-treated mice. In the colon, mucosal regeneration was observed in 2/9 mice of the 25 mg/kg neratinib-treated group and 4/9 mice of the 12.5 mg/kg afatinib-treated group (Fig. 4b). These findings indicated prior injuries in the colon intestine. In the eyeball, atrophy in the corneal epithelium was observed in 1/9 mouse of the 6.25 and 25 mg/kg neratinib-treated groups, and 5/9 mice of the 6.25 and 12.5 mg/kg afatinib-treated groups (Fig. 4c). Neither of these toxicological findings was observed with 12.5 and 25 mg/kg S-222611-treated mice. These results indicated that S-222611 should be more effective than irreversible inhibitors when compared at doses that are not associated with toxic changes.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.