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 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.Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile.These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.Show MeSH
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Mentions: As EGFR and HER2 are expressed in many types of cancer, S-222611 was tested for its antitumor activity in various cancer models in vivo (Fig. 2a–d, Table S2). In HER2-overexpressing human breast cancer models, S-222611 showed remarkable antitumor activity in the BT474 tumor model (Fig. 2a) and complete growth inhibition at 50 mg/kg even in the relatively less sensitive MDA-MB-361 tumor model (Fig. 2b). The antitumor activity of lapatinib for EGFR-dominant cancer was limited compared with that for HER2-expressing cancer.(28,29) S-222611 showed potent antitumor activity even in EGFR-dominant tumor models (Fig. 2c,d and Table S2). Moreover, the treatment with a higher dose of S-222611 (>50 mg/kg) completely inhibited the growth of tumors or caused marked tumor regression in most of the models tested. These results indicate that S-222611 should be an effective treatment in a variety of tumor types.
Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.