Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC

LKB 1是一种丝氨酸/苏氨酸激酶，位于染色体19p13.3。LKB 1的遗传突变导致 上升到Peutz-Jeghers综合征，一种以胃肠道良性血管瘤为特征的疾病， 易患某些癌症，包括肺癌。虽然LKB 1的获得性突变相对罕见， 在大多数散发性肿瘤类型中，超过30%的NSCLC在LKB 1中具有失活突变。最近 对LKB 1功能的研究进展将该基因置于一种新的信号通路的顶端， 用于抑制哺乳动物雷帕霉素靶蛋白（mTOR）。目前的证据支持这样一种模式， LKB 1通过依次激活AMP调节激酶介导mTOR的抑制 （AMPK）和肿瘤抑制因子TSC 2，在肿瘤发生的条件下覆盖PIS激酶/AKT存活信号传导。 低能量或营养缺乏。文献数据和我们实验室的初步工作 这表明LKB 1功能受损的细胞对微管靶向的 化疗剂。这些数据使我们假设LKB 1可能充当传感器 LKB 1介导的mTOR活性抑制可能促进微管完整性的细胞凋亡。 对微管导向剂的反应。LKB 1也在C-末端的CAAX基序处法尼基化， 可能是法尼基转移酶抑制剂的靶点。因此，LKB 1及其下游效应物可能代表 现有的药物如干扰微管动力学的紫杉烷和 当代信号转导抑制剂如mTOR抑制剂和法尼基转移酶 抑制剂的 我们假设LKB 1/AMPK/TSC 2通路是NSCLC中常见的失活靶点， 这一通路的完整性是NSCLC对选择性化疗敏感性的关键决定因素， 化疗剂。本提案的目标是：（i）确定LKB 1/AMPK的频率 非小细胞肺癌信号通路改变，（ii）确定LKB 1/AMPK通路改变对 NSCLC对所选化疗剂的反应，以及（iii）确定是否 LKB 1/AMPK/TSC通路改变可预测NSCLC对治疗药物的临床反应 患者更好地理解NSCLC中LKB 1/AMPK/TSC 2信号转导改变的后果 其在化疗敏感性中的作用将为内在药物的作用机制提供新的见解 这可能为将来实施“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.