Therapeutic potential of mTOR kinase inhibitors in lung cancer

描述(申请人提供)：雷帕霉素(MTOR)的哺乳动物靶标是一种丝氨酸-苏氨酸激酶，在促进细胞生长和存活方面发挥关键作用，主要是通过与其他蛋白质相互作用，如Raptor(形成mTOR复合体1，mTORC1)和Rictor(形成mTOR复合体2，mTORC2)。该通路在包括肺癌在内的人类癌症中经常被激活，因此是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(雷帕洛格)是mTORC1的特异性变构抑制剂。尽管其中一些是FDA批准的治疗肾癌的药物，但拉帕洛格在大多数其他肿瘤类型中的单药活性充其量也是适度的。因此，人们花了大量的精力来开发mTOR的ATP竞争性抑制剂(即mTOR激酶抑制剂；TORKinibs)，它们同时抑制mTORC1和mTORC2的功能。新的TORKinibs可能会提供额外的临床益处，因为它们抑制了作为Akt S473激酶的mTORC2。事实上，TORKinibs具有良好的临床前抗癌活性。然而，TORKinibs在肺癌中的活性还没有报道，也没有很好的研究。此外，基因改变对细胞对TORKinibs敏感性的影响尚不清楚。在这项建议中，我们将检验TORKinibs单独或联合其他癌症治疗药物将有效治疗非小细胞肺癌(NSCLC)的假设，通过实现三个特定目标：1)评估TORKinibs在体内外抑制NSCLC细胞生长的效果和抑制mTOR信号的作用；2)证明CDKN2A基因及其途径的基因改变对细胞对TORKinibs的反应的影响；以及3)确定TORKinibs是否与TRAIL合作促进NSCLC细胞的凋亡并增强其抗癌活性并了解其潜在的机制。这项建议将使我们能够评估新的TORKinibs单独或与其他药物联合治疗NSCLC的潜力，并确定CDKN2A或CDK4的基因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.