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The Dual-Targeted HER1/HER2 Tyrosine Kinase Inhibitor Lapatinib Strongly Potentiates the Cardiac Myocyte-Damaging Effects of Doxorubicin

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Abstract

The anticancer drug lapatinib (Tykerb) is a dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways that have been shown in clinical trials to display some cardiotoxicity. Because trastuzumab also targets HER2 receptors, the lapatinib/doxorubicin combination provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Using a neonatal rat cardiac myocyte model, we have investigated the ability of lapatinib alone and in combination with doxorubicin to damage myocytes. Lapatinib treatment alone only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of nanomolar lapatinib concentrations. Lapatinib alone treatment decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased myocyte damage. As measured by flow cytometry, lapatinib-treated myocytes displayed an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations and, thus, increasing myocyte damage. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity.

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Abbreviations

ABC:

ATP-binding-cassette

ACC:

Acetyl-Coenzyme A carboxylase

ACCα and ACCβ:

Alpha and beta isoforms of ACC

AKT:

v-akt murine thymoma viral oncogene homolog 1 kinase

AMPK:

AMP-activated protein kinase

DCF:

2′,7′-Dichlorofluorescin

DF-x :

Dulbecco’s modified eagle medium/Ham’s F-12 medium 1:1 where x is % (v/v) serum

ERK:

Extracellular signal-regulated kinase

K d :

Kinase-binding dissociation constant

LDH:

Lactate dehydrogenase

pACCα and pACCβ:

Phosphorylated alpha and beta isoforms of ACC

P-gp:

P-glycoprotein

PBS:

Dulbecco’s phosphate-buffered saline (pH 7.4)

λEx and λEm :

Excitation and emission wavelengths, respectively

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Acknowledgments

This work was supported by a CIHR grant and a Canada Research Chair in Drug Development to Brian Hasinoff.

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  1. Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada

    Brian B. Hasinoff, Daywin Patel & Xing Wu

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  1. Brian B. Hasinoff
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  2. Daywin Patel
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Correspondence to Brian B. Hasinoff.

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Hasinoff, B.B., Patel, D. & Wu, X. The Dual-Targeted HER1/HER2 Tyrosine Kinase Inhibitor Lapatinib Strongly Potentiates the Cardiac Myocyte-Damaging Effects of Doxorubicin. Cardiovasc Toxicol 13, 33–47 (2013). https://doi.org/10.1007/s12012-012-9183-x

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