Targeting erlotinib-resistant lung cancer with rational combination treatments

肺癌是癌症死亡的主要原因，并且在很大程度上对标准化疗是难治的。 选择性EGFR抑制剂（例如，厄洛替尼）在10 - 20%的非小细胞肺癌中引起临床反应 （NSCLC），其与激活EGFR突变相关，然而， 厄普替尼单药治疗无效的患者。EGFR在大多数NSCLC中表达，表明 它可能仍然是一个重要的治疗目标，与其他治疗相结合。我们建议 通过确定与第二种治疗的合理组合来扩大厄洛替尼的临床效用， NSCLC患者的另一个子集。目的1：确定厄洛替尼与抗肿瘤药物联合治疗的疗效。 第二次治疗。通过使用108个厄洛替尼难治性NSCLC细胞系，我们将测试厄洛替尼加化疗剂的能力。 产生细胞抑制或细胞毒性活性的额外处理。我们将重点关注MET的抑制剂， IGF-1、激酶以及HSP 90。我们还将测试电离辐射与厄洛替尼协同作用的能力。 总之，这些研究有望揭示对所提出的治疗敏感的NSCLC亚群。 联合治疗目的2：建立厄洛替尼和阿托伐他汀联合治疗的机制。 第二药剂抑制细胞存活。在对联合治疗具有协同应答的NSCLC细胞系中， 我们将检验这一假设，即抑制可能对EGFR衍生的 信号产生合成杀伤力。我们还将描述非小细胞肺癌中辐射诱导的EGFR活化 对厄洛替尼和放射敏感，我们将证实这种EGFR激活也见于 NSCLC患者取出。我们假设在高敏感细胞系中观察到的细胞死亡类似于 先前描述的EGFR突变细胞对厄洛替尼的凋亡反应。目标3：查明 预测对治疗组合的敏感性的生物标志物。在对联合治疗敏感的细胞系中， 我们将敏感性与：（i）NSCLC中复发性基因突变，（ii）比较基因组 杂交阵列数据，和（iii）基因表达谱。我们的发现有望为临床试验提供信息 对于获得性厄洛替尼/吉非替尼耐药的NSCLC患者（开发中|n其中项目4和5 孢子），并最终导致基因型驱动的新型药物组合或分子靶向试验 肿瘤表现出原发性厄洛替尼耐药的患者的放射治疗。

Lung cancer is the leading cause of cancer deaths, and is largely refractory to standard chemotherapy. Selective EGFR inhibitors (e.g., erlotinib) elicit clinical responses in 10-20% of non-small cell lung cancers (NSCLC), which correlates with activating EGFR mutations, However, there remains a large fraction of patients for which erlptinib, as monotherapy, is ineffective. EGFR is expressed in most NSCLCs, suggesting that it may still be an important therapeutic target, in conjunction with additional treatment. We propose to expand the clinical utility of erlotinib by identifying a rational combination with a second treatment to benefit an additional subset of NSCLC patients. Aim 1: To establish the efficacy of erlotinib in combination with a second treatment. By utilizing 108 NSCLC erlotinib-refractory cell lines, we will test the ability of erlotinib plus an additional treatment to produce cytostatic or cytotoxic activity. We will focus on inhibitors of the MET and IGF-1, kinases, as well as HSP90. We will also test the abiHty of ionizing radiation to synergize with erlotinib. Together, these studies are expected to reveal subsets of NSCLCs that are sensitive to the proposed combination therapies. Aim 2: To establish mechanisms by which combination treatment with erlotinib and a second agent inhibits cell survival. In NSCLC cell lines with synergistic response to combination treatment, we will test the hypothesis that inhibition of survival pathways that may be redundant to EGFR-derived signals produces synthetic lethality. We will also characterize radiation-induced EGFR activation in NSCLCs that are sensitive to erlotinib and radiation, and we will confirm that such EGFR activation is also seen in NSCLC patient explants. We hypothesize that cell death observed in highly sensitive cell lines resembles the previously described apoptotic response to erlotinib in cells with EGFR mutations. Aim 3: To identify jiomarkers that predict sensitivity to treatment combinations. In cell lines sensitive to combination treatment, we will correlate sensitivity with: (i) recurrent gene mutations in NSCLC, (ii) comparative genome hybridization array data, and (iii) gene expression profiles. Our findings are expected to inform clinical trials for NSCLC patients with acquired erlotinib/gefitinib resistance (in development |n Projects 4 and 5 of this SPORE) and ultimately lead to genotype-driven trials of novel drug combinations or molecularly targeted radiation therapy in patients whose tumors exhibit primary erlotinib resistance.