Aberrant CRTC activation as a unique vulnerability of lung cancer with LKB1 inactivation

项目总结/摘要 肺癌是全世界癌症死亡的主要原因，迫切需要有效的治疗。 治疗全面的基因分析显示，LKB 1（STK 11）肿瘤抑制基因是 在非小细胞肺癌（NSCLC）中经常发生改变，NSCLC是肺癌的一种主要形式。肺癌伴LKB 1 失活具有独特的生物学和行为;然而，目前还没有针对此的靶向疗法。 独特的，普遍的肺癌分子亚型。虽然传统上很难将不活跃或 由于缺乏肿瘤抑制因子，其效应途径可能为治疗提供合理的靶向机会。 干预 LKB 1基因编码丝氨酸/苏氨酸激酶，调节细胞生长、极性和代谢。一个 LKB 1的重要功能是负调节三种CREB转录共激活因子（CRTC 1， 2，3），在新陈代谢，衰老和癌症中起着至关重要的作用。我们之前发现LKB 1缺失会导致 增强的去磷酸化CRTCs水平，随后易位到细胞核并促进 CREB依赖基因在癌细胞中的转录。然而，这种异常活跃的CRTC的重要性- CREB信号轴及其在肺癌中的潜在机制仍然缺乏特征性， 知识对于发现新的治疗策略至关重要。因此，我们的研究旨在 通过阐明这种LKB 1失活诱导的信号传导的意义来弥合这一重大差距， 肺癌的发病机制基于我们已发表的和初步的数据，我们假设异常的CRTC 激活是肺恶性肿瘤中LKB 1缺失的核心驱动因素， LKB 1失活的肺癌。这一假设将通过两个具体目标进行检验。目标1将阐明 异常激活的CRTC-CREB信号在LKB 1失活的肺癌中的功能意义， 目的2：阐明LKB 1失活的肺癌中CRTC-CREB异常激活的机制。 这些拟议研究的成功完成将揭示新的机制和功能的见解， CRTC异常激活在LKB 1失活肺癌的发展和进展中的作用我们预计 这些努力将验证CRTCs作为治疗靶点，揭示新的治疗策略，并有助于 我们对LKB 1失活的癌症生物学机制的理解。

Project Summary/Abstract Lung cancer is the leading cause of cancer deaths worldwide and there is an urgent need for effective treatment. Comprehensive genetic profiling has revealed that the LKB1 (STK11) tumor suppressor gene is frequently altered in non–small cell lung cancer (NSCLC), a major form of lung cancer. Lung cancer with LKB1 inactivation has distinct biology and behaviors; however, no targeted therapies are currently available for this unique, prevalent molecular subtype of lung cancer. While it is traditionally challenging to target an inactive or absent tumor suppressor, its effector pathways likely present rational target opportunities for therapeutic intervention. The LKB1 gene encodes a serine/threonine kinase regulating cell growth, polarity, and metabolism. An important function of LKB1 is negatively regulating a family of three CREB transcriptional co-activators (CRTC1, 2,3), which have crucial roles in metabolism, aging and cancer. We previously discovered that LKB1 loss causes enhanced levels of dephosphorylated CRTCs that subsequently translocate to the nucleus and promote transcription of CREB-dependent genes in cancer cells. However, the importance of this aberrantly active CRTC- CREB signaling axis and its underlying mechanisms in lung cancer remain poorly characterized and such knowledge will be crucial in uncovering new therapeutic strategies. Therefore, our proposed research is aimed to bridge this significant gap by elucidating this LKB1 inactivation-induced signaling for its significance and mechanisms in lung cancer. Building on our published and preliminary data, we hypothesize that aberrant CRTC activation is a core driver event that underlies LKB1 loss in lung malignancies, presenting a unique vulnerability of LKB1-inactivated lung cancers. This hypothesis will be tested by two specific aims. Aim 1 will elucidate the functional significance of aberrantly activated CRTC-CREB signaling in lung cancers with LKB1 inactivation, and Aim 2 will define the mechanisms of aberrant CRTC-CREB activation in lung cancers with LKB1 inactivation. The successful completion of these proposed studies will uncover new mechanistic and functional insights into aberrant CRTC activation in the development and progression of LKB1-inactivated lung cancer. We anticipate that these efforts will validate CRTCs as a therapeutic target, reveal novel therapeutic strategies, and contribute to our mechanistic understanding of the biology of cancer with LKB1 inactivation.