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

项目摘要/摘要 肺癌是世界范围内癌症死亡的主要原因，迫切需要有效的 治疗。综合遗传图谱显示，LKB1(STK11)抑癌基因是 在非小细胞肺癌(NSCLC)中经常发生改变，非小细胞肺癌是肺癌的主要形式。肺癌伴发LKB1 灭活有不同的生物学和行为；然而，目前还没有针对这一点的针对性治疗方法。 肺癌的独特的、流行的分子亚型。虽然传统上以非活动或非活动的 缺乏肿瘤抑制因子，其效应通路可能为治疗提供合理的靶向机会 干预。 LKB1基因编码一种丝氨酸/苏氨酸激酶，调节细胞生长、极性和新陈代谢。一个 LKB1的重要功能是负调控三个CREB转录共激活因子家族(CRTC1， 2，3)，它们在新陈代谢、衰老和癌症中起着至关重要的作用。我们之前发现，LKB1的丢失会导致 增强去磷酸化CRTC的水平，随后移位到细胞核并促进 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未得到充分研究 知识对于发现新的治疗策略将是至关重要的。因此，我们提出的研究旨在 通过阐明LKB1失活诱导的信号转导的重要性来弥合这一重大差距 肺癌的发病机制。基于我们公布的初步数据，我们假设异常的CRTC 激活是肺部恶性肿瘤中LKB1丢失的核心驱动事件，呈现出独特的脆弱性 LKB1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 CRTC-CREB信号异常激活在LKB1失活肺癌中的功能意义 目的2明确LKB1失活肺癌中CRTC-CREB异常激活的机制。 这些拟议研究的成功完成将揭示出对 CRTC异常激活在LKB1失活肺癌发生发展中的作用我们期待着 这些努力将验证CRTC作为治疗靶点，揭示新的治疗策略，并有助于 有助于我们从机制上理解LKB1失活的癌症生物学。

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.