Development of the novel peptide-based therapeutics for the molecular targeting agent-resistant lung cancers.

我们的目的是描述耐药和敏感的肺腺癌细胞对吉非替尼的不同分子反应，以了解基于分子信息的治疗方法。因此，我们发现在对吉非替尼敏感的肺腺癌克隆中p14^&lt；ARF和GT；的表达有特异性的增加，而在吉非替尼耐药的克隆中没有这一点。此外，我们还发现38-65个氨基酸残基是线粒体p14^-lt；ARF&gt；(p14 38-65 A.A.)的功能核心，它降低了线粒体膜电位，引起caspase-9的激活。覆盖p1438-65a.的合成肽诱导对吉非替尼耐药克隆的生长抑制，而不影响非肿瘤细胞。这些发现表明，p14^lt；arf&gt；38-65年A.A.在吉非替尼对EGFR突变的肺腺癌细胞的药理作用中起着关键作用，并在吉非替尼耐药癌症的治疗中具有潜在的实用价值。

We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. Consequently, we found a specific increase in p14^<ARF> expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, we identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14^<ARF> (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a.induced growth suppression of the gefitinib-resistant clones without affecting non-neoplastic cells. These findings suggest that the region of p14^<ARF> 38-65 a.a. is critical in the pharmacological action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.