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C. Minichsdorfer
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-100 - Combination of Pitavastatin and Erlotinib Induces Apoptosis and Growth Arrest in Non-Small Cell Lung Cancer (NSCLC)-Celllines (ID 494)
09:30 - 17:00 | Author(s): C. Minichsdorfer
- Abstract
Background:
Primary resistance against epithelial growth factor receptor (EGFR) targetet therapy is often caused by K-Ras mutations or amplification of the MET-oncogene. HMG-CoA reductase inhibitors (statins) are well tolerated drug mainly prescribed for the the primary and secondary prophylaxis of coronary artery disease. However, the majority of statins are metabolized in the liver by Cyp3A4, which may lead to interactions with Erlotinib a tyrosin kinase inhibitor (TKI) which targets the EGFR. Therefore we tested the efficacy of Erlotinib in combination with Pitavastatin, which is metabolized by Cyp3A4, for the treatment of primary Erlotinib-resistant NSCLC celllines.
Methods:
Experiments were carried out with human NSCLC celllines A549 (K-RAS mutation), Calu-6 (K-RAS mutation, P53 mutation), HCC 827 (EGFR mutation, Erlotinib sensitive) and H1993 (MET amplification). Apoptosis was measured by the activity of caspase 3 by cleavage of specific fluorescent caspase substrates, by binding of AnnexinV by FACS analysis or by the cleavage of PARP by Western blot. Inhibition of growth was assessed by MTS assays. The effect of either drug alone or in combination on phosphorylation of AKT and ERK1/2 was evaluated by Western blot.
Results:
Inhibition of growth by erlotinib was seen in the sensitive cell line HCC 827 but not in A549, Calu6 and H1993. Pitavastatin led to growth inhibition in all 4 cell lines investigated in a dose dependant manner. However, the combination of Pitavastatin and Erlotinib was significantly more effective than either drug alone. Erlotinib and Pitavastatin did not induce apoptosis when used as single agents in A549, Calu6 or H1993. When a combination of TKI and Pitavastatin was used we observed significantly increased caspase 3 activity and a higher rate of annexin V positive cells. Moreover an increased cleavage of PARP was shown in the combination treatment. Taken together we could show increased rate of apoptosis when Erlotinib and Pitavastatin where used in combination. Importantly the activation of survival pathways mediated by phosphorylation of AKT was markedly decreased, by the combined treatment in A549, Calu6 and H1993 cells. ERK 1/2 phosphorylation was reduced in H1993 and Calu6 cells upon combined treatment.
Conclusion:
Our data indicate, that the treatment of primary EGFR-TKI resistant cells (A549, Calu6 and H1993) with Erlotinib in combination with Pitavastatin leads to growth arrest and an induced rate of apoptosis.
