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

总结 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EGFR酪氨酸激酶抑制剂（EGFR-TKI）。AZD 9291（TAGRISSO ™或 奥希替尼）代表第三代EGFR-TKI，是FDA批准用于EGFR突变患者的药物 通过T790 M突变对第一代EGFR-TKI和EGFR产生耐药性的NSCLC 突变阳性晚期NSCLC作为一线治疗。不幸的是，患者最终会复发， 在临床上对AZD 9291产生耐药性，导致疾病进展。因此，更好地了解 克服AZD 9291耐药性的潜在机制和有效策略的开发是一个 诊所中未满足需求的紧急和关键领域。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作为转录因子发挥作用，调节 许多基因的产物参与调节各种生理过程，如细胞 存活、增殖、分化、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表达，因此是恶性肿瘤的主要驱动因素。 细胞生长和增殖。c-Myc表达与癌细胞对肿瘤细胞增殖的反应或敏感性相关。 化疗或放疗。然而，没有研究将c-Myc与第三代靶向治疗联系起来 EGFR-TKI。我们强有力的初步数据支持了c-Myc调节可能发挥作用的总体假设。 在介导AZD 9291对EGFRm NSCLC的治疗疗效和发展中的关键作用 因此，靶向c-Myc将是克服AZD 9291获得性耐药的有效策略。 获得性耐药AZD 9291和其他EGFR-TKI。这一假设将通过完成 以下3个具体目的：1）了解EGFR突变体中c-Myc减少的机制 通过AZD 9291或其他EGFR-TKI对NSCLC细胞的作用; 2）证明c-Myc的生物学意义 抑制EGFR靶向治疗;和3）开发有效的治疗方案，以克服 通过靶向c-Myc获得对AZD 9291的抗性。本研究的目的是了解 AZD 9291和其他EGFR-TKI降低c-Myc水平的机制，以证明AZD 9291和其他EGFR-TKI的生物学效应。 c-Myc抑制在EGFR靶向癌症治疗中的意义;并开发有效的策略， 通过靶向c-Myc克服对AZD 9291的获得性耐药性。这一建议具有很高的科学性， 翻译意义这项研究的结果可以立即转化为临床治疗， 对AZD 9291或其他EGFR-TKI获得性耐药的NSCLC患者。 1

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