Lapatinib potentiates cytotoxicity of  YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter

Abstract

Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

“…Its overexpression has been reported to be related to poor response to chemotherapy and poor overall survival in leukemia patients [11, 12]. Based on this situation, various kinds of drugs including lapatinib [13], cediranib [14], alectinib [15], and gefitinib [16] have been reported to reverse MDR by inhibiting the function of ABCB1. Although MDR modulators have been extensively studied, no MDR modulator has ever been approved by FDA for clinic application.…”

Drug-adapted cancer cell lines reveal drug-induced heterogeneity and enable the identification of biomarker candidates for the acquired resistance setting

“…Most studies focus on biomarkers that indicate whether a certain cancer cell (population) is likely to respond to a certain treatment, but not on biomarkers that indicate early that a current therapy has stopped working. This also applies to the previous studies that investigated the efficacy of YM155 in neuroblastoma [13,14,16].…”

“…Increased ABCB1 expression (mediates YM155 efflux) and decreased SLC35F2 expression (mediates cellular YM155 uptake) were identified as YM155 resistance mechanisms in panels of YM155-naïve cell lines that displayed varying levels of these proteins and in functional studies [13,15,16,34], which was further supported by our analysis of GDSC and CTRP data [28,29]. Despite their roles in determining YM155 resistance, however, cellular ABCB1 or SLC35F2 levels did not enable the prediction of whether an individual cell line would be sensitive to YM155 or not.…”

“…Increased cellular ABCB1 (mediates YM155 efflux) levels and decreased SLC35F2 (mediates cellular YM155 uptake) levels have previously been identified as important YM155 resistance mechanisms [13,15,16,34]. To further investigate the relationship between ABCB1 and SLC35F2 levels and YM155 sensitivity, we compared the YM155 sensitivity in cell lines that displayed low or high expression of the respective genes using GDSC and CTRP data.…”

“…A number of studies have investigated the potential of YM155 against neuroblastoma cells [13][14][15][16]. Neuroblastoma is the most common extracranial solid childhood tumor.…”