Targeting the LKB1-AMPK pathway in melanoma: Mechanism and preclinical evaluation

靶向黑色素瘤中的 LKB1-AMPK 通路：机制和临床前评估

• 批准号: 8723596
• 负责人: Bin Zheng
• 金额: $ 28.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723596
• 关键词: Targeting; LKB1; AMPK; pathway; melanoma

DESCRIPTION (provided by applicant): Melanoma is a major form of skin cancer and arises from the malignant transformation of melanocytes. One of the most commonly mutated genes in melanoma is B-RAF (~50%), which encodes a member of the RAF protein kinase family and an intermediate in the RAS-RAF-MEK-ERK signaling cascade. Findings from recent clinical trials using B-RAF inhibitors in malignant melanoma have shown great promise for B-RAF-targeted therapy. However, the clinical findings also revealed development of resistance to B-RAF inhibitor as a major therapeutic challenge. We have recently discovered a novel bi-directional crosstalk between B-RAF and the tumor suppressor LKB1-AMPK pathway, another important signaling pathway involved in the regulation of cancer cell growth, proliferation and survival. Activators of the LKB1-AMPK pathway (such as metformin, a common anti-diabetes drug, and its analog phenformin) have recently shown anti-tumor activities in cell culture studies and mouse models. Based on our recent findings, we hypothesize that combination treatment of B- RAF inhibitors and AMPK activators will offer therapeutic advantages for the treatment of melanoma over the B-RAF inhibitor single agent therapy, and holds the potential for overcoming drug resistance to B-RAF inhibitors. The goal of this proposal is to define the biochemical mechanism underlying the attenuation of BRAF-MEK-ERK signaling by AMPK and to assess pre-clinically the therapeutic benefit of combining AMPK activators with B-RAF inhibitors for melanoma treatment. In aim 1, we will further elucidate the biochemical mechanism underlying the regulation of ERK signaling by AMPK and study its role in the regulation of cell proliferation and survival in response to energy stress. In aim 2, we will evaluate the combinatory effect of AMPK activators and B-RAF inhibitors on inhibiting tumor growth in xenografts of human melanoma cell lines and in a B-RAF-driven genetically engineered mouse model. Finally, in aim 3, we will investigate the role of the LKB1-AMPK signaling in defining both acquired and intrinsic resistance to B-RAF inhibitors in melanoma therapy and assess the potential of AMPK activators on delaying the emergence of resistance to B-RAF inhibitors.

描述（由申请人提供）：黑色素瘤是皮肤癌的一种主要形式，由黑色素细胞的恶性转化引起。黑色素瘤中最常见的突变基因之一是 B-RAF（约 50%），它编码 RAF 蛋白激酶家族的成员以及 RAS-RAF-MEK-ERK 信号级联的中间体。最近使用 B-RAF 抑制剂治疗恶性黑色素瘤的临床试验结果表明，B-RAF 靶向治疗具有巨大的前景。然而，临床研究结果还表明，对 B-RAF 抑制剂产生耐药性是一个主要的治疗挑战。我们最近发现了 B-RAF 和肿瘤抑制因子 LKB1-AMPK 通路之间的一种新型双向串扰，这是另一个参与调节癌细胞生长、增殖和存活的重要信号通路。 LKB1-AMPK 通路的激活剂（例如常见的抗糖尿病药物二甲双胍及其类似物苯乙双胍）最近在细胞培养研究和小鼠模型中显示出抗肿瘤活性。根据我们最近的研究结果，我们假设 B-RAF 抑制剂和 AMPK 激活剂的联合治疗将为黑色素瘤的治疗提供优于 B-RAF 抑制剂单药治疗的治疗优势，并具有克服 B-RAF 耐药性的潜力抑制剂。该提案的目标是确定 AMPK 减弱 BRAF-MEK-ERK 信号传导的生化机制，并评估临床前联合 AMPK 激活剂与 B-RAF 抑制剂治疗黑色素瘤的治疗效果。在目标1中，我们将进一步阐明AMPK调节ERK信号传导的生化机制，并研究其在响应能量应激时调节细胞增殖和存活的作用。在目标 2 中，我们将评估 AMPK 激活剂和 B-RAF 抑制剂对抑制人类黑色素瘤细胞系异种移植物和 B-RAF 驱动的基因工程小鼠模型中肿瘤生长的组合作用。最后，在目标 3 中，我们将研究 LKB1-AMPK 信号传导在定义黑色素瘤治疗中对 B-RAF 抑制剂的获得性耐药性和内在耐药性中的作用，并评估 AMPK 激活剂在延迟 B-RAF 抑制剂耐药性出现方面的潜力。