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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

Selectivity of TAK-285 (1 μM) kinase inhibitory activity.
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Figure 1: Selectivity of TAK-285 (1 μM) kinase inhibitory activity.

Mentions: TAK-285 demonstrated inhibitory activity against HER2 and EGFR kinases with IC50 values for HER2 and EGFR of 17 nmol/L (95% CI 12-24) and 23 nmol/L (95% CI 18-30), respectively. In a panel of human kinases, TAK-285 showed weak inhibition (0‒50%) against 88 of 96 kinases tested, moderate inhibition (50-80%) against EGFR (L858R) and alkaline phosphatase, and strong inhibition (80‒100%) against HER family kinases including EGFR(L861Q) as well as against CDK3/cyclin E and Flt3 (Figure 1).


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)

Selectivity of TAK-285 (1 μM) kinase inhibitory activity.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Selectivity of TAK-285 (1 μM) kinase inhibitory activity.
Mentions: TAK-285 demonstrated inhibitory activity against HER2 and EGFR kinases with IC50 values for HER2 and EGFR of 17 nmol/L (95% CI 12-24) and 23 nmol/L (95% CI 18-30), respectively. In a panel of human kinases, TAK-285 showed weak inhibition (0‒50%) against 88 of 96 kinases tested, moderate inhibition (50-80%) against EGFR (L858R) and alkaline phosphatase, and strong inhibition (80‒100%) against HER family kinases including EGFR(L861Q) as well as against CDK3/cyclin E and Flt3 (Figure 1).

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