Targeting autophagy to increase the sensitivity of LKB1-deficient lung tumors to angiogenesis inhibitor

靶向自噬提高 LKB1 缺陷型肺部肿瘤对血管生成抑制剂的敏感性

• 批准号: 10770658
• 负责人: Yanxiang Guo
• 金额: $ 22.02万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10770658
• 关键词: Targeting; autophagy; increase; sensitivity; LKB1

ABSTRACT Lung cancer is the leading cancer killer worldwide, with non-small cell lung cancer (NSCLC) accounting for more than 85% of these cases. KRAS and LKB1 are the two most frequent mutations detected in lung cancer patients. Lung cancer patients bearing co-mutations of KRAS and LKB1 show increased aggressiveness, a high frequency of metastases, and resistance to all standard therapies. Cancer cells acquire nutrients from circulating blood. Angiogenesis inhibitors, which block the growth of blood vessels, have been used for lung cancer treatment. However, multiple preclinical as well as clinical studies have reported that LKB1 depletion confers resistance to angiogenesis inhibitors, regardless of whether or not receiving chemotherapy. One of acquired resistance to antiangiogenics stems from tumor adaptations by induction of metabolic symbiosis. Autophagy is a process that cell eats itself to generate building blocks, energy, and redox homeostasis, and for elimination of waste in response to metabolic stress, such as nutrient depletion. Many studies including our group have proved that in response to extracellular nutrient deprivation, cancer cells can scavenge nutrients through autophagy- mediated intracellular recycling for tumor growth, proliferation, survival, and malignancy. Therefore, simultaneously eliminating nutrient availability from both intracellular and extracellular sources could be an innovative strategy for a successful cancer treatment. In particular, we recently demonstrated that autophagy is upregulated in Kras-mutant Lkb1-deficient (KL) lung tumor and autophagy inhibition is synthetically lethal in KL- mediated tumorigenesis. Moreover, anti-tumor effect by autophagy ablation is much more profound in Lkb1- deficient KL lung tumor than Lkb1 wild type (WT) KP (Kras-mutant p53-deficient) lung tumor. Based on above rationale and preliminary studies, we formed central hypothesis: autophagy-mediated intracellular recycling compensates for nutrient deprivation caused by angiogenesis inhibitor to support the survival and growth of KL lung tumor. We will: 1) determine the role and mechanism of cell-autonomous autophagy in conferring resistance of KL lung tumor to angiogenesis inhibitor; and 2) Determine if targeting autophagy can sensitize Lkb1-deficient KL lung tumor, but not Lkb1-WT KP lung tumor, to angiogenesis inhibitor. Our study will determine if LKB1 mutations could be explored as a predictive biomarker for precision lung cancer therapy using the combination of autophagy inhibitor and angiogenesis inhibitor. Once our hypothesis is confirmed in preclinical mouse models, the novel therapy of autophagy inhibitor hydroxychloroquine combined with angiogenesis inhibitor Bevacizumab can be naturally and immediately translated into clinical trials for treating lung cancer patients harboring co- mutations of KRAS and LKB1.

抽象的 肺癌是全世界领先的癌症杀手，非小细胞肺癌（NSCLC）占更多 这些案件中的85％。 KRAS和LKB1是在肺癌患者中检测到的两个最常见的突变。 具有KRAS和LKB1共突变的肺癌患者表现出侵略性提高，很高 转移的频率和对所有标准疗法的抗性。癌细胞从循环中获取营养 血。阻断血管生长的血管生成抑制剂已用于肺癌 治疗。但是，多次临床前和临床研究报告说LKB1耗竭 不管是否接受化疗，对血管生成抑制剂的抗性。一个被收购的人 对抗血管生成的抗性源于诱导代谢共生的肿瘤适应。自噬是 细胞会饮食以产生构建基块，能量和氧化还原稳态的过程，并消除 响应代谢应激的浪费，例如营养耗竭。包括我们小组在内的许多研究已证明 为了响应细胞外营养剥夺，癌细胞可以通过自噬来清除营养 介导的细胞内回收，用于肿瘤生长，增殖，生存和恶性肿瘤。所以， 同时消除细胞内和细胞外来源的营养可用性可能是 成功进行癌症治疗的创新策略。特别是，我们最近证明了自噬是 在KRAS突变的LKB1缺陷型（KL）肺肿瘤和自噬抑制中上调的KL-综合性致死 介导的肿瘤发生。此外，自噬消融的抗肿瘤效应在LKB1- 比LKB1野生型（WT）KP（KRAS-突变p53缺陷型）肺肿瘤缺乏KL肺肿瘤。基于上述 理由和初步研究，我们形成了中心假设：自噬介导的细胞内回收 补偿由血管生成抑制剂引起的营养剥夺，以支持KL的存活和生长 肺部肿瘤。我们将：1）确定细胞自主自噬的作用和机制在赋予抗性中 KL肺肿瘤至血管生成抑制剂； 2）确定靶向自噬是否可以使LKB1缺陷敏感 KL肺肿瘤，但不是LKB1-WT KP肺肿瘤，致血管生成抑制剂。我们的研究将确定LKB1是否 可以将突变作为预测性生物标志物，用于使用该组合的精确肺癌治疗 自噬抑制剂和血管生成抑制剂。一旦我们的假设在临床前小鼠模型中得到证实， 自噬抑制剂羟基氯喹的新型疗法与血管生成抑制剂贝伐单抗结合 可以自然并立即转化为临床试验，用于治疗伴有共同的肺癌患者 KRAS和LKB1的突变。