Antitumor activity of bortezomib in human cancer cells with acquired resistance to anti-epidermal growth factor receptor tyrosine kinase inhibitors

作者：Morgillo Floriana; D'Aiuto Elena; Troiani Teresa; Martinelli Erika; Cascone Tina; De Palma Raffaele; Orditura Michele; De Vita Ferdinando; Ciardiello Fortunato^*

来源：Lung Cancer, 2011, 71(3): 283-290.

DOI：10.1016/j.lungcan.2010.06.005

• EGFR
• Proteasome
• Bortezomib
• Erlotinib
• Gefitinib

The understanding of the molecular mechanisms which regulate cancer cell sensitivity to epidermal growth factor receptor (EGFR) inhibitors is necessary for the optimal use of these drugs in cancer treatment. We developed an in vitro model of acquired resistance to two EGFR tyrosine kinase inhibitors (TKI), erlotinib and gefitinib, by continuously treating the human non-small cell lung cancer (NSCLC) cell line CALU-3 with escalating doses of each drug. In these two EGFR inhibitor-resistant cancer cell lines a significant increase in the expression of activated, phosphorylated AKT and of survivin compared to parental cells was observed. Treatment with several agents known to target directly or indirectly the AKT signalling pathway did not affect significantly EGFR inhibitor-resistant cancer cell proliferation. In contrast, bortezomib, a proteasome inhibitor, induced a significant inhibition of cancer cell growth and an increase in apoptosis in EGFR inhibitor-resistant cancer cells as compared to treatment with LY294002, a PI3K inhibitor, suggesting that, in addition to interference with AKT signalling, other mechanisms are involved in the pro-apoptotic effects of bortezomib. Bortezomib treatment activated endoplasmic reticulum (ER) stress-mediated apoptosis, as demonstrated by the induction of GADD153, an ER stress-inducible transcription factor, and of the death receptor DR5, in EGFR inhibitor-resistant cells, but not in parental cells. This effect resulted in the activation of the extrinsic apoptotic pathway, as shown by caspase 8 dependent-PARP and bid cleavage. Bortezomib significantly inhibited the growth of EGFR inhibitor-resistant CALU-3 cells which were established as subcutaneous tumor xenografts in athymic nude mice. These results suggest that bortezomib treatment could be a useful approach to overcome resistance to anti-EGFR therapies.

• 出版日期2011-3