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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 activity of TAK-285. A, B: in mouse and C, D: rat xenograft models.
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Figure 3: Antitumor activity of TAK-285. A, B: in mouse and C, D: rat xenograft models.

Mentions: TAK-285 in vivo antitumor activity in murine xenograft models is shown in Figure 3. TAK-285 (100 mg/kg BID) inhibited BT-474 breast tumors and 4-1ST gastric tumor growth with T/C values of 29% and 11%, respectively, compared to controls (Figure 3A, B). Similarly, in rat xenografts, TAK-285 inhibited growth of tumors that overexpressed HER2 (4-1ST) or EGFR (A-431) with T/C values of 14% and 13%, respectively, at a dose of 12.5 mg/kg BID (Figure 3C, D). In other experiments (not shown), the pharmacokinetic profile for TAK-285 showed much greater drug exposure in rats compared with mice, thus requiring lower doses in the rat xenograft model.


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 activity of TAK-285. A, B: in mouse and C, D: rat xenograft models.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Antitumor activity of TAK-285. A, B: in mouse and C, D: rat xenograft models.
Mentions: TAK-285 in vivo antitumor activity in murine xenograft models is shown in Figure 3. TAK-285 (100 mg/kg BID) inhibited BT-474 breast tumors and 4-1ST gastric tumor growth with T/C values of 29% and 11%, respectively, compared to controls (Figure 3A, B). Similarly, in rat xenografts, TAK-285 inhibited growth of tumors that overexpressed HER2 (4-1ST) or EGFR (A-431) with T/C values of 14% and 13%, respectively, at a dose of 12.5 mg/kg BID (Figure 3C, D). In other experiments (not shown), the pharmacokinetic profile for TAK-285 showed much greater drug exposure in rats compared with mice, thus requiring lower doses in the rat xenograft model.

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