Therapeutic potential of mTOR kinase inhibitors in lung cancer

描述（由申请人提供）：哺乳动物雷帕霉素（mTOR）靶点是一种丝氨酸-苏氨酸激酶，在促进细胞生长和存活中起着关键作用，主要通过与其他蛋白质如raptor（形成mTOR复合物1，mTORC1）和rictor（形成mTOR复合物2，mTORC2）的相互作用。该途径在包括肺癌在内的人类癌症中经常被激活，因此代表了一个有吸引力的癌症治疗靶点。传统的mTOR抑制剂雷帕霉素及其类似物（rapalog）是mTORC1的特异性变构抑制剂。尽管其中一些是fda批准的用于治疗肾癌的药物，但rapalogs在大多数其他肿瘤类型中的单药活性充其量是适度的。因此，人们一直在努力开发atp竞争性mTOR抑制剂（即mTOR激酶抑制剂；TORKinibs），它可以抑制mTORC1和mTORC2的功能。新型TORKinibs可能提供额外的临床益处，因为它们抑制mTORC2， mTORC2作为Akt S473激酶发挥作用。事实上，TORKinibs具有很有前景的临床前抗癌活性。然而，TORKinibs在肺癌中的活性尚未被报道或充分研究。此外，基因改变对细胞对TORKinibs敏感性的影响尚不清楚。在本研究中，我们将通过以下三个具体目标来验证TORKinibs单独或与其他癌症治疗药物联合治疗非小细胞肺癌（NSCLC），特别是CDKN2A突变或CDK4扩增的假设：1)评估TORKinibs在体外和体内对非小细胞肺癌细胞生长的抑制作用及其对mTOR信号的抑制作用；2)验证CDKN2A基因的基因改变及其通路对细胞对TORKinibs反应的影响；3)确定TORKinibs是否与TRAIL协同增加NSCLC细胞凋亡并增强其抗肿瘤活性，并了解其机制。该建议将使我们能够评估新型TORKinibs单独或与其他药物联合治疗NSCLC的治疗潜力，并确定CDKN2A或CDK4基因改变对这组药物的细胞反应的影响。

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.