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.

摘要 肺癌是全球头号癌症杀手，非小细胞肺癌(NSCLC)占比更高 其中85%以上的案件。KRAS和LKB1是在肺癌患者中检测到的两个最常见的突变。 携带KRAS和LKB1共突变的肺癌患者表现出更高的侵袭性， 转移的频率，以及对所有标准治疗的抗药性。癌细胞从循环中获取营养物质 血。血管生成抑制药可阻止血管生长，已用于肺癌。 治疗。然而，多项临床前和临床研究报告称，LKB1的耗竭使 对血管生成抑制剂的抵抗力，无论是否接受化疗。获得者之一 对抗血管生成药物的抵抗源于通过诱导代谢共生而产生的肿瘤适应。自噬是 细胞吞噬自身以产生积木、能量和氧化还原动态平衡的过程，以及消除 应对新陈代谢压力的废物，如营养耗竭。包括我们小组在内的许多研究已经证明 作为对细胞外营养缺乏的反应，癌细胞可以通过自噬来清除营养- 调节细胞内循环以促进肿瘤的生长、增殖、存活和恶性。因此， 同时消除胞内和胞外来源的养分供应可能是一个 成功治疗癌症的创新策略。特别是，我们最近证明了自噬是 在Kras突变型Lkb1缺陷型(KL)肺癌中表达上调，自噬抑制在Kras突变型KL中合成致死 介导的肿瘤发生。此外，自噬消融的抗肿瘤作用在Lkb1细胞中更为明显。 缺陷型KL肺癌高于野生型(WT)Kras突变型(Kras-突变型P53-缺失)肺癌。基于以上几点 理论基础和初步研究，我们形成了中心假说：自噬介导的细胞内循环 补偿血管生成抑制剂引起的营养剥夺以支持KL的生存和生长 肺部肿瘤。我们将：1)确定细胞自主自噬在赋予抗性中的作用和机制 KL肺癌对血管生成抑制物的敏感性；以及2)确定靶向自噬是否可以增敏Lkb1缺陷 KL肺癌，而不是Lkb1-WT KP肺癌，对血管生成抑制物有抑制作用。我们的研究将确定LKB1 利用联合应用，突变可作为精确肺癌治疗的预测生物标记物。 自噬抑制因子和血管生成抑制因子。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联合血管生成抑制剂贝伐珠单抗的新疗法 可自然并立即转化为治疗肺癌患者的临床试验 KRAS和LKB1基因突变。