Therapeutic potential of mTOR kinase inhibitors in lung cancer

描述（由申请人提供）：雷帕霉素的哺乳动物靶标（mTOR）是一种丝氨酸-苏氨酸激酶，主要通过与其他蛋白质如raptor（形成mTOR复合物1，mTORC 1）和rictor（形成mTOR复合物2，mTORC 2）相互作用，在促进细胞生长和存活中发挥关键作用。该途径在包括肺癌在内的人类癌症中经常被激活，因此代表了有吸引力的癌症治疗靶点。常规mTOR抑制剂雷帕霉素及其类似物（rapalogs）是mTORC 1的特异性变构抑制剂。虽然其中一些是FDA批准的治疗肾癌的药物，但雷帕霉素类似物在大多数其他肿瘤类型中的单药活性最多也就是中等水平。因此，已经做出了巨大的努力来开发mTOR的ATP竞争性抑制剂（即，mTOR激酶抑制剂; TORKinibs），其抑制mTORC 1和mTORC 2两者的功能。新的TORKinib可以提供额外的临床益处，因为它们抑制mTORC 2，其作为Akt S473激酶发挥作用。事实上，TORKinib具有有希望的临床前抗癌活性。然而，TORKinibs在肺癌中的活性尚未报道或充分研究。此外，遗传改变对细胞对TORKinib敏感性的影响是未知的。在本提案中，我们将通过实现三个具体目标来检验TORKinib单独或与其他癌症治疗剂组合将有效治疗非小细胞肺癌（NSCLC），特别是具有CDKN 2A突变或CDK 4扩增的那些的假设：1）评估TORKinib在体外和体内抗NSCLC细胞生长的功效以及它们对抑制mTOR信号传导的作用; 2）证明CDKN 2A基因及其通路的遗传改变对TORKinib的细胞应答的影响;和3）确定TORKinib是否与TRAIL协同作用以增加NSCLC中的细胞凋亡并发挥增强的抗癌活性，并了解潜在的机制。这一提议将使我们能够评估新型TORKinib单独或与其他药物联合治疗NSCLC的治疗潜力，并确定CDKN 2A或CDK 4的遗传改变对细胞对这组药物的反应的影响。

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) is a serine-threonine kinase and plays a critical role in promoting cell growth and survival, primarily through interactions with other proteins such as raptor (forming mTOR complex 1, mTORC1) and rictor (forming mTOR complex 2, mTORC2). This pathway is frequently activated in human cancers including lung cancer and thus represents an attractive cancer therapeutic target. The conventional mTOR inhibitors rapamycin and its analogues (rapalogs) are specific allosteric inhibitors of mTORC1. Although some of them are FDA-approved drugs for treatment of renal cancer, the single-agent activity of rapalogs in most other tumor types has been modest at best. Thus, great effort has been made to develop ATP-competitive inhibitors of mTOR (i.e., mTOR kinase inhibitors; TORKinibs), which inhibit function of both mTORC1 and mTORC2. The novel TORKinibs may provide additional clinical benefits since they inhibit mTORC2, which functions as an Akt S473 kinase. Indeed, TORKinibs possess promising preclinical anticancer activity. However, the activity of TORKinibs in lung cancer has not been reported or well studied. Moreover, the impact of genetic alterations on cell sensitivity to TORKinibs is unknown. In this proposal, we will test the hypothesis that TORKinibs alone or in combination with other cancer therapeutic agents will be effective in treatment of non-small cell lung cancer (NSCLC), particularly those with CDKN2A mutation or CDK4 amplification, by accomplishing three specific aims: 1) To evaluate the efficacy of TORKinibs against the growth of NSCLC cells in vitro and in vivo and their effects on repressing mTOR signaling; 2) To demonstrate the impact of genetic alteration of CDKN2A gene and its pathway on cell responses to TORKinibs; and 3) To determine whether TORKinibs cooperates with TRAIL to augment apoptosis and to exert enhance anticancer activity in NSCLC and understand the underlying mechanisms. This proposal will allow us to evaluate the therapeutic potential of the novel TORKinibs alone or in combination with others against NSCLC, and to determine the impact of genetic alteration of CDKN2A or CDK4 on cell responses to this group of agents.