Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC

LKB1是一种位于19p13.3染色体上的丝氨酸/苏氨酸激酶。LKB1基因的遗传性突变使 上升为Peutz-Jeghers综合征，一种以胃肠道良性血肿为特征的疾病 易患某些癌症，包括肺癌。虽然LKB1的获得性突变在 在大多数散发性肿瘤类型中，超过30%的非小细胞肺癌存在LKB1失活突变。近期 LKB1功能的研究进展将该基因置于一条新的信号通路的顶端，最终 用于抑制哺乳动物的雷帕霉素靶标(MTOR)。目前的证据支持这样一种模型 LKB1通过顺序激活AMP调节的激酶介导mTOR的抑制 (AMPK)和肿瘤抑制因子TSC2，在以下条件下覆盖PIS激酶/AKT生存信号 缺乏能量或营养。文献中的数据和我们实验室的初步工作 提示LKB1功能受损的细胞对微管靶向作用的抵抗力更强 化疗药物。这些数据使我们假设LKB1可能作为一种传感器 微管完整性，而LKB1介导的mTOR活性抑制可能促进细胞凋亡 对微管导向药的反应。LKB1在C末端的CAAX基序上也被法尼化，并且 可能是法尼基转移酶抑制剂的靶点。因此，LKB1及其下游效应器可能代表 现有的像紫杉烷这样干扰微管动力学的药剂和 当代信号转导抑制剂，如mTOR抑制剂和法尼基转移酶 抑制剂。 我们假设LKB1/AMPK/TSC2通路是非小细胞肺癌和非小细胞肺癌中常见的失活靶点。 这一途径的完整性是非小细胞肺癌对所选药物敏感性的关键决定因素 化疗药物。这项建议的目标是(I)确定LKB1/AMPK的频率 非小细胞肺癌中信号通路的改变，(Ii)确定LKB1/AMPK通路改变对 非小细胞肺癌对选定化疗药物的反应，以及(Iii)决定是否 LKB1/AMPK/TSC通路改变可预测NSCLC对治疗药物的临床疗效 病人。更好地了解LKB1/AMPK/TSC2信号改变在非小细胞肺癌中的后果 而它在化疗敏感性中的作用将为深入了解内在药物的机制(S)提供新的视角 并可能为未来实施“个体化”治疗提供分子基础。

LKB1 is a serine/threonine kinase located on chromosome 19p13.3. Inherited mutations in LKB1 give rise to Peutz-Jeghers syndrome, a disorder characterized by benign hemartomas of Gl tract and a predisposition to certain cancers, including lung. While acquired mutations in LKB1 are relatively rare in most sporadic tumor types, more than 30% of NSCLC harbor inactivating mutations in LKB1. Recent progress on the function of LKB1 places this gene at the apex of a novel signaling pathway that ultimately serves to inhibit the mammalian Target of Rapamycin (mTOR). Current evidence supports a model in which LKB1 mediates the suppression of mTOR through the sequential activation of AMP regulated kinase (AMPK) and the tumor suppressor TSC2, overriding PIS kinase/AKT survival signaling under conditions of low energy or nutrient deprivation. Data from the literature and preliminary work from our laboratories indicate that cells with compromised LKB1 function are more resistant to effects of microtubule-targeted chemotherapeutic agents. These data have led us to hypothesize that LKB1 may act as a sensor of microtubule integrity, and that LKB1 mediated suppression of mTOR activity may promote apoptosis in response to microtubule-directed agents. LKB1 is also farnesylated at a CAAX motif in the C-terminus and may be a target of farnesyltransferase inhibitors. Thus, LKB1 and its downstream effectors may represent a convergence point between existing agents like the taxanes that interfere with microtubule dynamics and contemporary signal transduction inhibitors such as the mTOR inhibitors and the farnesyltransferase inhibitors. It is our hypothesis that LKB1/AMPK/TSC2 pathway is a frequent target of inactivation in NSCLC and that the integrity of this pathway is a critical determinant of the sensitivity of NSCLC to selected chemotherapeutic agents. The goals of this proposal are to (i) determine the frequency of LKB1/AMPK signaling pathway alterations in NSCLC, (ii) determine the impact of LKB1/AMPK pathway alterations on the response of NSCLC to selected chemotherapeutic agents, and (iii) determine whether LKB1/AMPK/TSC pathway alterations are predictive of clinical response to therapeutic agents in NSCLC patients. A better understanding of the consequences of altered LKB1/AMPK/TSC2 signaling in NSCLC and its role in chemosensitivity will provide novel insight into the mechanism(s) underlying intrinsic drug resistance and may provide a molecular basis for future implementation of "individualized" therapies.