Lapatinib is a dual targeting (EGFR/HER2) small molecule tyrosine kinase inhibitor (TKI) approved for the treatment of HER2+ breast cancer. Lapatinib treatment can often lead to acquired resistance and refractory disease. There is no data available on the sensitivity of lapatinib-resistant breast cancer cells to immune cell-mediated cytotoxicity. To investigate the consequences of a lapatinib resistant phenotype on the immune response, we examined T-ADCC and the expression levels of immune-related proteins in a cell line model of lapatinib-resistant HER2+ breast cancer.
Lapatinib-resistant SKBR3 cells (SKBR3-Lap) were generated by continuous exposure to 250nM lapatinib for 6 months alongside untreated parental cells (SKBR3-Par). FACS-based assays employing peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers were used to measure direct PBMC-mediated cytotoxicity and T-ADCC. Comparative DNA microarray studies (SK-Par vs. SK-LAP) identified differentially expressed immune-related genes which were subsequently examined at the protein level by Western blot.
T-ADCC was 45-50% lower in SKBR3-Lap compared to the SKBR3-Par cell line at the three effector to target cell ratios examined - 1:1 (p = 0.01), 5:1 (p = 0.001) and 10:1 (p = 0.024). Direct immune cell-mediated cytotoxicity was low (
Resistance to lapatinib is associated with an attenuated T- ADCC response and an altered profile of immune-related proteins in this HER2+ breast cancer model. Further investigation is warranted to explore if targeting proteins such as A2AR or PD-L1 could play a role in ADCC response in this model.
Clinical trial identification
Legal entity responsible for the study
Cancer Biotherapeutics, National Institute for Cellular Biotechnology, Dublin City University
Cancer Clinical Research Trust
N. O'Donovan: Research funding from GlaxoSmithKline. J. Crown: Honoraria from Novartis. Research funding from Roche and GlaxoSmithKline. D. Collins: Currently funded by a Roche Postdoctoral Fellowship and has received funding from Roche Products Ireland Ltd. as part of the IRCSET Enterprise Partnership Scheme. All other authors have declared no conflicts of interest.
N. O\'Donovan: Research funding from GlaxoSmithKline. J. Crown: Honoraria from Novartis. Research funding from Roche and GlaxoSmithKline. D. Collins: Currently funded by a Roche Postdoctoral Fellowship and has received funding from Roche Products Ireland Ltd. as part of the IRCSET Enterprise Partnership Scheme. All other authors have declared no conflicts of interest.