Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells

Abstract

Antibodies and small molecule tyrosine kinase inhibitors targeting ErbB2 exhibit distinct, noncross resistant mechanisms of action. Here, apoptosis of ErbB2-overexpressing breast cancer cells was enhanced by combining lapatinib, an inhibitor of ErbB1 and ErbB2 tyrosine kinases, with anti-ErbB2 antibodies, including (i) trastuzumab, a humanized monoclonal antibody, and (ii) pAb, rabbit polyclonal antisera generated by vaccination with a human ErbB2 fusion protein. Treating ErbB2-overexpressing breast cancer cell lines with a relatively low concentration of lapatinib alone resulted in a minimal increase in tumor cell apoptosis with an associated decrease in steady-state protein levels of p-ErbB2, p-Akt, p-Erk1/2, and notably survivin, compared to baseline. Exposure to pAb alone reduced total ErbB2 protein, disrupting ErbB3 transactivation, leading to a marked inhibition of p-Akt; however, survivin protein levels remained unchanged and apoptosis only increased slightly. Treatment with trastuzumab alone had relatively little effect on survivin and apoptosis was unaffected. Combining lapatinib with either pAb or trastuzumab markedly downregulated survivin protein and enhanced tumor cell apoptosis. The association between the inhibition of survivin and enhanced apoptosis following the combination of ErbB2-targeted therapies provides a biological effect in order to identify therapeutic strategies that promote tumor cell apoptosis and might improve clinical response.

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

“…In the present study ( Figs. 1 and 2) and in accordance with previous data (3), we demonstrate that Trastuzumab and Pertuzumab had a primarily cytostatic rather than a cytotoxic function (26,37). However, both antibodies slightly enhance Lapatinib-caused apoptotic cell death (Fig.…”

“…This characteristic is advantageous, because therapy resistance and recurrence of malignant cell growth have been suggested to be due to compensation of specific molecule targeting by activation of redundant pathways (26). However, modular ErbB receptor targeting that includes cell treatment with Lapatinib, Trastuzumab, and Pertuzumab can be considered a flexible therapeutic approach, which enables cellular resistance due to the proproliferative impact of receptor-specific growth factors to be overcome.…”

“…2), but also in terms of reversibility of Lapatinib-caused cell-cycle exit (Fig. 1C) (25,26). A differential expression level of EGFR in Her2-overexpressing BT474 and SK-BR-3 (7) might be-at least in part-responsible for a distinct sensitivity to anti-ErbB receptor targeting (8).…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…An ERBB2 kinase inhibitor such as lapatinib might alter or abolish the effect of trastuzumab on BCL-X family proteins in cardiomyocytes, raising the interesting possibility that lapatinib might ameliorate trastuzumab cardiotoxicity. This would provide additional motivation for a trial that combines these two agents 39 . Several of these pathways converge on antiapoptotic mechanisms: the Ras-ERK pathway stimulates the expression of BCL2, STAT5 activates BCL-X, and Akt inhibits BCL2-antagonist of cell death (BAD) and forkhead box O3A (FOXO3A).…”

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…One such approach would be to give the two agents in combination. In preclinical models, the combination is superior to single drug treatment and enhanced apoptosis has been proposed as a mechanism (Xia et al, 2005;Konecny et al, 2006). In the clinic, a phase III study comparing the efficacy of lapatinib versus the combination of lapatinib and trastuzumab in patients with advanced trastuzumab-resistant HER2-positive breast cancer has shown improved clinical outcome with the combination (O'Shaughnessy et al, 2008).…”