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Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model.

Nakayama A, Takagi S, Yusa T, Yaguchi M, Hayashi A, Tamura T, Kawakita Y, Ishikawa T, Ohta Y - J Cancer (2013)

Bottom Line: Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux.TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model.TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib.

View Article: PubMed Central - PubMed

Affiliation: Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555 Japan.

ABSTRACT
Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.

No MeSH data available.


Related in: MedlinePlus

Antitumor efficacy of TAK-285 and lapatinib in murine subcutaneous xenografts. Inoculation of tumor on day 0 and drug treatment began on day 18.
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Figure 4: Antitumor efficacy of TAK-285 and lapatinib in murine subcutaneous xenografts. Inoculation of tumor on day 0 and drug treatment began on day 18.

Mentions: TAK-285 has been shown to effectively inhibit proliferation and viability of BT-474 cells with an IC50 of 17 nmol/L (Table 1), and under these in vitro conditions, possessed comparable cytotoxicity to lapatinib (IC50 ~10 nmol/L) 25. Consequently, studies were initiated to assess the in vivo activity of TAK-285 and lapatinib in mice bearing subcutaneous xenografts of BT474 human breast cancer cells that over-express HER2. In these studies, TAK-285 effectively inhibited subcutaneous xenograft growth when administered at a dose of 100 mg/kg BID, and after 2 weeks of treatment, the T/C ratio was 27% (Figure 4) and lapatinib at the same dose showed similar efficacy in this subcutaneous human tumor xenograft model system. Both treatment regimens were well tolerated, and there was no treatment-related mortality.


Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model.

Nakayama A, Takagi S, Yusa T, Yaguchi M, Hayashi A, Tamura T, Kawakita Y, Ishikawa T, Ohta Y - J Cancer (2013)

Antitumor efficacy of TAK-285 and lapatinib in murine subcutaneous xenografts. Inoculation of tumor on day 0 and drug treatment began on day 18.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3753530&req=5

Figure 4: Antitumor efficacy of TAK-285 and lapatinib in murine subcutaneous xenografts. Inoculation of tumor on day 0 and drug treatment began on day 18.
Mentions: TAK-285 has been shown to effectively inhibit proliferation and viability of BT-474 cells with an IC50 of 17 nmol/L (Table 1), and under these in vitro conditions, possessed comparable cytotoxicity to lapatinib (IC50 ~10 nmol/L) 25. Consequently, studies were initiated to assess the in vivo activity of TAK-285 and lapatinib in mice bearing subcutaneous xenografts of BT474 human breast cancer cells that over-express HER2. In these studies, TAK-285 effectively inhibited subcutaneous xenograft growth when administered at a dose of 100 mg/kg BID, and after 2 weeks of treatment, the T/C ratio was 27% (Figure 4) and lapatinib at the same dose showed similar efficacy in this subcutaneous human tumor xenograft model system. Both treatment regimens were well tolerated, and there was no treatment-related mortality.

Bottom Line: Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux.TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model.TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib.

View Article: PubMed Central - PubMed

Affiliation: Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555 Japan.

ABSTRACT
Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.

No MeSH data available.


Related in: MedlinePlus