Background: Lapatinib targets human epidermal growth factor-receptor (EGFR) and Her2/neu receptor tyrosine-kinases and hence is under investigation in multimodal therapy concepts of advanced head and neck squamous cell carcinoma (HNSCC). We studied combined effects of lapatinib and cisplatin on colony formation (CF) of epithelial cells of individual HNSCC in short term ex vivo assays.
Materials and methods: Biopsies of HNSCC were minced, collagenase-digested and exposed to serial lapatinib dilutions or solvent control (DMSO). The same lapatinib concentrations were tested in mixture with 1.67 μM, 3.33 or 6.67 μM cisplatin. After α 72-h incubation, adherent cells were ethanol-fixed and epithelial cells were stained using a Cy2™-labeled pan-cytokeratin antibody; then fluorescent colonies were counted.
Results: 33 of 51 ex vivo growing HNSCC (64.7%) exhibited epithelial CF allowing for cut-off detection. Lowest cut-off (complete chemotherapeutical suppressed CF) was noted at 6.25 μM lapatinib in three HNSCC (9.1%). The percentage of HNSCC achieving cut-off by 6.67 μM cisplatin (21.2%) was raised by addition of lapatinib at 6.25, 12.5, and 25 μM up to 33%, 45.5%, and 60.6%, respectively. However, we observed significant inter-individual different dose-response curves of HNSCC in response to lapatinib, e.g. variation in concentrations inhibiting CF to 50% (IC(50)) was 60-fold. At the individual level, antagonism, additivity, and synergism were detected as appropriate models describing the mode of action of cisplatin and lapatinib mixtures.
Conclusion: Lapatinib suppresses CF of epithelial HNSCC cells, and in combination with cisplatin its efficacy is increased. However, caution is advisable due to significant heterogeneity in the response of HNSCC to lapatinib alone and when combined with cisplatin.