探討一種新穎合成化合物PT262在克服人類非小細胞肺癌之EGFR突變的抗藥作用

Abstract

目前非小細胞肺癌患者對於藥物產生抗藥性是臨床癌症治療的主要瓶頸。當病人的表皮生長因子受體上具有exon 19 缺失或是exon 21的單點突變時會對於第一代與第二代的酪氨酸激酶抑制劑，如Gefitinib及Erlotinib反應良好，然而這類的藥物治療一段時間後表皮生長因子受體基因會發生突變，而產生抗藥性，其中T790M是最為常見的突變位點。此外，癌幹的特性也被認為是非小細胞肺癌產生抗藥性的重要因素。因此發展新的化合物來克服非小細胞肺癌的抗藥性是高度需要的。在這個研究中我們使用一種新穎由 5,8-quinolinedione衍生而來的化合物PT262，有潛力克服非小細胞肺癌的T790M及癌幹性的作用。在實驗中發現，PT262具有誘導抗藥性細胞株H1975 (含EGFR T790M突變) 死亡及凋亡的能力，且能抑制Survivin的蛋白表現並誘發caspase 3及PARP的活化導致細胞凋亡。除此之外，這個化合物也能抑制在肺癌細胞中癌幹性蛋白Oct4的表現。我們並發現PT262能有效抑制由臨床非小細胞肺癌病人之肺肋脊液中分離出的肺癌細胞之生存率。根據上述的結果，這個新穎的化合物有潛力進一步研究及探討在克服非小細胞肺癌之抗藥性作用。

Drug resistance has become bottleneck in clinical cancer therapy of non-small cell lung carcinoma (NSCLC) patients. The mutations of epidermal growth factor receptor (EGFR) on exon 19 deletion and exon 21 point mutation are respond well to the first and second generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as Gefitinib and Erlotinib for NSCLC therapy; however, patients acquired the T790M mutation of EGFR will induce drug resistance. In addition, cancer stemness properties are also a pivotal factor of drug resistance in NSCLC. Accordingly, development of novel compounds for overcoming drug resistance of NSCLC is highly desired. In this study, we show a novel synthetic compound PT262 that derived from 5,8-quinolinedione has potential in overcoming drug resistance of EGFR (T790M) and cancerous stemness in NSCLC. This new compound can induce cell death and apoptosis in the drug-resistant H1975 cells, which contained EGFR (T790M). This compound inhibited Survivin protein expression and conversely increased the active caspase 3 and cleaved PARP for apoptosis induction. In addition, this compound can inhibit the stemness protein expression of Oct4 in lung cancer cells. Moreover, it can also decrease the cell viability in drug resistance NSCLC cells, which were separated from pleural effusion of NSCLC. Taken together, we develop a novel compound, which has potential to further investigate for overcoming drug resistance in NSCLC.