Rational Combined Inhibition of NF-kB and EGFR to Optimize Lung Cancer Treatment

项目摘要。表皮生长因子激酶结构域的体细胞激活突变 EGFR受体（EGFR）驱动10-20%的非小细胞肺癌（NSCLC）的生长，NSCLC是肺癌的主要原因。 癌症死亡率1，2. EGFR酪氨酸激酶抑制剂（TKI）在许多EGFR突变型NSCLC中有效 患者1，2.然而，这种临床疗效受到先天性、适应性和获得性EGFR TKI耐药性的限制， 阻止患者长期生存3 -6。确定限制EGFR TKI反应的机制对于 改善临床结果。当EGFR突变患者对初始EGFR TKI治疗确实有应答时， 通常是不完整的，因为一些肿瘤细胞持续存在，并作为残留疾病存活， 理解机制5，7-10。这些残留的疾病细胞形成EGFR TKI耐受细胞库， 最终导致获得性抵抗。现在迫切需要确定分子事件， 这些EGFR突变肿瘤细胞在初始EGFR TKI治疗期间作为残留疾病持续存在， 阻断该过程的治疗策略，从而改善EGFR TKI的幅度和持续时间 患者的反应。从一开始，该项目的目标就是： NF-kB通过其限制EGFR TKI应答和（B）鉴定NF-kB的小分子抑制剂，其可以有效地 并安全地增强EGFR突变型NSCLC的EGFR TKI应答。在该项目资助的正在进行的研究中，我们 在实现这些目标方面取得了进展7，11-20。我们的初步研究表明NF-kB是一种很有前途的 靶向克服先天性和预防获得性EGFR TKI耐药性，通过实验揭示了一种新的 EGFR TKI诱导的NF-κ B适应性激活在驱动不完全应答和残留疾病中的作用 这是获得性抵抗的前奏我们发现新型直接NF-kB抑制剂PBS-1086可以与 EGFR TKI安全地用于增强缓解、抑制残留疾病和预防获得性耐药， 临床前EGFR突变型NSCLC细胞和动物模型7.根据我们的工作，PBS-1086正在进行 临床发展。我们现在试图将这个项目扩展到新的方向，以剖析 NF-kB介导对EGFR TKI治疗的耐受性，以促进促进获得性耐药的残留疾病。 我们将测试NF-kB驱动无法解释的和新出现的耐药特征的创新假设。 EGFR TKI治疗期间持续存在的细胞：（1）细胞凋亡抗性（Aim 1）和（2）EGFR TKI的从头获得 耐药突变（Aim 2）7- 9，21。这些通过NF-kB激活产生的持续细胞特征可以相互作用。 通过同时使肿瘤细胞可塑性、存活和遗传适应性得以增强， EGFR TKI耐药性的演变。我们正在寻求一个长期的战略，以确定NF-κ B的功能，在限制 对EGFR TKI治疗的反应，以指导未来合理使用NF-κ B信号传导或其抑制剂的努力。 关键目标，以便更好地限制耐药性的演变并改善临床结果。

PROJECT ABSTRACT. Somatic activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) drive the growth of 10-20% of non-small cell lung cancers (NSCLCs), the leading cause of cancer mortality1,2. EGFR tyrosine kinase inhibitors (TKIs) are effective in many EGFR-mutant NSCLC patients1,2. However, this clinical efficacy is limited by innate, adaptive, and acquired EGFR TKI resistance that prevents long-term patient survival3-6. Identifying the mechanisms that limit EGFR TKI response is essential to improve clinical outcomes. When EGFR-mutant patients do respond to initial EGFR TKI treatment, the responses are typically incomplete because some tumor cells persist and survive as residual disease through poorly understood mechanisms5,7-10. These residual disease cells form a reservoir of EGFR TKI-tolerant cells that eventually grow to cause acquired resistance. There is an urgent need to define the molecular events that allow these EGFR-mutant tumor cells to persist as residual disease during initial EGFR TKI treatment in order to design therapeutic strategies to intercept this process and thereby improve the magnitude and duration of EGFR TKI response in patients. From its inception, the goals of this project have been to: (a) understand the mechanism(s) by which NF-kB limits EGFR TKI response and (b) identify a small molecule inhibitor of NF-kB that can effectively and safely enhance EGFR TKI response in EGFR-mutant NSCLC. In ongoing studies funded by this project, we have made progress towards achieving these goals7,11-20. Our initial studies demonstrated NF-kB is a promising target to overcome innate and prevent acquired EGFR TKI resistance, through experiments that revealed a novel role for EGFR TKI-induced adaptive activation of NF-kB in driving incomplete response and the residual disease that is a prelude to acquired resistance. We showed the novel direct NF-kB inhibitor, PBS-1086, can be combined safely with an EGFR TKI to enhance response, suppress residual disease, and prevent acquired resistance in preclinical EGFR-mutant NSCLC cellular and animal models7. Based on our work, PBS-1086 is undergoing clinical development. We now seek to extend this project in novel directions to dissect the mechanism by which NF-kB mediates tolerance to EGFR TKI treatment to promote the residual disease that fuels acquired resistance. We will test the innovative hypothesis that NF-kB drives unexplained and emerging features of drug-tolerant persister cells during EGFR TKI treatment: (1) apoptotic resistance (Aim 1) and (2) de novo gain of EGFR TKI resistance mutations (Aim 2)7-9,21. These persister cell features arising via NF-kB activation could be mutually reinforcing by simultaneously enabling tumor cell plasticity, survival, and genetic adaptation to promote the evolution of EGFR TKI resistance. We are pursuing a long-term strategy to define the function of NF-kB in limiting response to EGFR TKI treatment to guide future efforts to rationally deploy inhibitors of NF-kB signaling or of its key targets in order to better constrain the evolution of resistance and improve clinical outcomes.