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

项目摘要。表皮生长因子激动域的体细胞激活突变 受体(EGFR)推动10%-20%的非小细胞肺癌(NSCLC)的生长，NSCLC是 癌症死亡率1.EGFR酪氨酸激酶抑制剂(TKIs)对许多EGFR突变的非小细胞肺癌有效 然而，这种临床疗效受到先天的、适应性的和获得性的EGFR TKI抵抗的限制 防止患者长期存活3-6个月。确定限制EGFR TKI反应的机制对于 改善临床结果。当EGFR突变患者对最初的EGFR TKI治疗确实有效时，这些反应 通常是不完整的，因为一些肿瘤细胞持续存在，并作为残留病存活下来 了解机制5，7-10。这些残留的疾病细胞形成了一个EGFR TKI耐受细胞的储存库 最终成长为后天的抵抗力。迫切需要定义分子事件，以使 这些EGFR突变的肿瘤细胞在最初的EGFR TKI治疗中作为残留病持续存在，以便设计 阻断这一过程从而改善EGFR TKI的大小和持续时间的治疗策略 患者的反应。从一开始，这个项目的目标就是：(A)了解机制(S) 通过核因子-kB限制EGFR TKI反应和(B)确定一种能够有效地抑制核因子-kB的小分子抑制剂 并安全地增强EGFR突变型NSCLC中的EGFR TKI反应。在这个项目资助的正在进行的研究中，我们 已经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，核因子-kB是一种很有前途的 通过实验发现了一种新的方法，目的是克服和预防获得性EGFR TKI耐药性 EGFR TKI诱导的核因子-kB适应性激活在驱动不完全应答和残留病中的作用 这是后天抵抗的前奏。我们证明了新型的直接核转录因子-kB抑制剂PBS-1086可以与 安全地使用EGFR TKI来增强反应，抑制残留疾病，并防止获得性耐药性 临床前EGFR突变的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。我们现在试图以新的方向扩展这个项目，以剖析 核因子-kB介导对EGFR TKI治疗的耐受性，以促进残留病，从而助长获得性耐药性。 我们将测试创新假设，即核因子-kB驱动未解释的和新出现的药物耐受特征 EGFR TKI治疗中的持久细胞：(1)抗凋亡(目标1)和(2)EGFR TKI的从头获得 耐药突变(目标2)7-9，21。这些通过核因子-kB激活产生的持久细胞特征可能是相互的 通过同时允许肿瘤细胞的可塑性、存活率和遗传适应来促进 EGFR TKI耐药的演变。我们正在推行一项长期战略，以确定核转录因子-kB在限制 对EGFR TKI治疗的反应，以指导未来合理部署核因子-kB信号或其抑制剂的努力 关键靶点，以便更好地限制耐药性的演变和改善临床结果。

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.