c-Myc modulation and its implications in EGFR-targeted cancer therapy

c-Myc 调节及其对 EGFR 靶向癌症治疗的影响

• 批准号: 10212350
• 负责人: Shi-Yong Sun
• 金额: $ 40.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212350
• 关键词: Address; Animal Model; Apoptotic; Area; Biochemical; Biological; Biological Assay; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Cell Survival; Chromosomal translocation; Clinic; Clinical; Clinical Treatment; Data; Development; Disease Progression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Event; Exons; FDA approved; Family member; Future; Gefitinib; Gene Amplification; Generations; Genes; Glutamine; Goals; Human; Human Genome; Immunity; In Vitro; Induction of Apoptosis; Knowledge; Link; MYC gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolism; Methods; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Outcome Study; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological Processes; Play; Point Mutation; Proteasome Inhibition; Proteins; Radiation therapy; Regimen; Regulation; Relapse; Resistance; Role; Safety; Science; Testing; Tissues; Translating; Treatment Efficacy; c-myc Genes; cancer cell; cell growth; chemotherapy; clinical translation; combinatorial; gene cloning; in vivo; inhibitor/antagonist; knock-down; knockout gene; lung cancer cell; mutant; overexpression; pre-clinical; research clinical testing; resistance mechanism; response; small molecular inhibitor; targeted cancer therapy; targeted treatment; therapeutic target; therapeutically effective; transcription factor; treatment comparison; tumor

SUMMARY An important milestone in the treatment of non-small cell lung cancer (NSCLC) is the discovery of epidermal growth factor receptor (EGFR) activating mutations as an effective therapeutic target and the successful development of EGFR tyrosine kinase inhibitors (EGFR-TKIs). AZD9291 (TAGRISSOTM or osimertinib) represents a 3rd generation EGFR-TKI and an FDA-approved drug for patients with EGFR mutant NSCLC that has become resistant to 1st generation EGFR-TKIs through the T790M mutation and for EGFR mutation-positive advanced NSCLC as a front line treatment. Unfortunately, patients eventually relapse and become resistant to AZD9291 in the clinic, resulting in disease progression. Thus, a better understanding of the underlying mechanisms and development of effective strategies to overcome AZD9291 resistance is an urgent and critical area of unmet need in the clinic. The C-MYC gene was the first Myc family member found in the human genome and its product, c-Myc, functions as a transcription factor to regulate the expression of many genes whose products are involved in the regulation of various physiological processes, such as cell survival, proliferation, differentiation, metabolism and host immunity. MYC is genetically activated and/or overexpressed in most types of human cancer including lung cancer and thus is a central driver of malignant cellular growth and proliferation. c-Myc expression is associated with response or sensitivity of cancer cells to chemotherapy or radiotherapy. However, no study has linked c-Myc to targeted therapy by third generation EGFR-TKIs. Our strong preliminary data support the overall hypothesis that c-Myc modulation may play a critical role in mediating therapeutic efficacy of AZD9291 against EGFRm NSCLC and the development of acquired resistance to AZD9291; accordingly, targeting c-Myc will be an effective strategy to overcome acquired resistance to AZD9291 and other EGFR-TKIs. This hypothesis will be tested by accomplishing the following 3 specific aims: 1) To understand the mechanism(s) by which c-Myc is reduced in EGFR mutant NSCLC cells by AZD9291 or other EGFR-TKIs; 2) To demonstrate the biological significance of c-Myc suppression in EGFR-targeted therapy; and 3) To develop effective therapeutic regimens to overcome acquired resistance to AZD9291 by targeting c-Myc. The objectives of this study are to understand the mechanisms by which AZD9291 and other EGFR-TKIs decrease c-Myc levels, to demonstrate the biological significance of c-Myc suppression during EGFR-targeted cancer therapy; and to develop effective strategies to overcome acquired resistance to AZD9291 by targeting c-Myc. This proposal is of high scientific and translational significance. The outcomes of this study can be immediately translated to the clinical treatment of NSCLC patients with acquired resistance to AZD9291 or other EGFR-TKIs. 1

摘要 非小细胞肺癌(NSCLC)治疗的一个重要里程碑是发现了 表皮生长因子受体(EGFR)激活突变作为有效的治疗靶点 成功开发了EGFR酪氨酸激酶抑制剂(EGFR-TKIs)。AZD9291(TAGRISSOTM或 Osimertinib)代表第三代EGFR-TKI，是FDA批准用于EGFR突变患者的药物 通过T790M突变和EGFR对第一代EGFR-TKIs产生耐药性的非小细胞肺癌 突变阳性的晚期非小细胞肺癌作为一线治疗。不幸的是，患者最终会复发并 在临床上对AZD9291产生抗药性，导致疾病进展。因此，更好地理解 克服AZD9291抗性的潜在机制和有效策略的发展是一种 诊所中未得到满足的紧急和关键需求领域。C-MYC基因是第一个发现的Myc家族成员 人类基因组及其产物c-Myc发挥转录因子的作用，调节 许多基因，其产物参与各种生理过程的调节，如细胞 生存、增殖、分化、新陈代谢和宿主免疫。MYC是基因激活的和/或 在包括肺癌在内的大多数类型的人类癌症中过度表达，因此是恶性的中心驱动因素 细胞的生长和增殖。C-Myc的表达与癌细胞对药物的反应或敏感性有关 化疗或放射治疗。然而，还没有研究将c-Myc与第三代靶向治疗联系起来。 EGFR-TKIs。我们强劲的初步数据支持c-Myc调制可能发挥作用的总体假设 AZD9291在介导EGFRm非小细胞肺癌疗效中的关键作用及进展 对AZD9291的获得性耐药；因此，靶向c-Myc将是克服 对AZD9291和其他EGFR-TKI的获得性耐药。这一假设将通过实现 目的：1)了解EGFR突变体中c-Myc降低的机制(S) AZD9291或其他EGFR-TKI介导的非小细胞肺癌细胞；2)论证c-Myc的生物学意义 EGFR靶向治疗中的抑制；以及3)开发有效的治疗方案来克服 通过靶向c-Myc获得对AZD9291的抗性。这项研究的目的是了解 AZD9291和其他EGFR-TKI降低c-Myc水平的机制，以证明生物学 C-Myc抑制在EGFR靶向癌症治疗中的意义；并开发有效的策略来 通过靶向c-Myc克服对AZD9291的获得性耐药性。这项建议具有很高的科学性和科学性 翻译意义。这项研究的结果可以立即转化为临床治疗 对AZD9291或其他EGFR-TKIs有获得性耐药的非小细胞肺癌患者。 1