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A.T. Madsen
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-073 - PD-L1 Expression Is Induced by MET in an Erlotinib-Resistant Cell Line with MET Amplification (ID 833)
09:30 - 09:30 | Author(s): A.T. Madsen
- Abstract
Background:
The programmed cell death receptor 1 (PD-1) and its ligand PD-L1 have proved to be of significant importance in lung cancer. Production of PD-L1 helps the cancer cells evade the immune system by inactivating T-cells. Clinical trials investigating the effect of treating lung cancer patients with monoclonal antibodies targeting the PD-L1 and PD-1 shows promising results. Expression of PD-L1 is associated with epidermal growth factor receptor (EGFR) mutational status. Further, expression can be significantly decreased by targeting EGFR with tyrosine kinase inhibitors (TKIs). In vitro studies suggest that this initial regulation of PD-L1 expression by EGFR occurs through the Erk pathway. Though, currently not much is known about expression of PD-L1 when TKI-resistance develops. We have developed erlotinib-resistant cell lines. The resistant cell line gained a MET amplification. We demonstrate that PD-L1 is increases in the resistant cells and that this increment is induced by MET signalling.
Methods:
The lung cancer cell line HCC827 with a deletion in exon 19 in the EGFR gene, was treated with increasing concentrations of erlotinib over 5 months until resistance developed. MET gene amplification in the resistant cells was confirmed by PCR. The resistant cell line was used for studying the effect of EGFR and MET inhibitors on PD-L1 expression.
Results:
The HCC827 erlotinib-resistant (ER) cell line gained a MET gene amplification, as seen in previous studies. In the initial phase of erlotinib treatment the expression of PD-L1 decreases. As the dose increases and resistance starts to develop the expression of PD-L1 increases. Activation of Erk is intact in HCC827ER as compared to the parental HCC827 cell line; most likely due to the activation of MET. When HCC827ER cells are treated with the MET inhibitor crizotinib, expression of PD-L1 decreases. When erlotinib is combined with crizotinib an additional effect on PD-L1 expression is observed. These results indicate that increased PD-L1 expression in erlotinib-resistant cell lines may be caused by activation of Erk through MET signalling.
Conclusion:
Our data demonstrates that Erk-dependent PD-L1 expression is increased in cells with erlotinib resistance caused by MET gene amplification. This mechanism might even be general and include several by-pass resistance mechanisms. Our findings suggest that the role of the PD-L1/PD-1 system should also be studied in erlotinib resistant tumors.
