Synthetic lethality by targeting the core senescent mechanism in lung cancer.

摘要 肺癌是全球癌症相关死亡的最常见原因。非小细胞肺癌（NSCLC） 占所有肺癌病例的85%，通常在晚期诊断，需要多模式 包括放射、化学疗法和靶向疗法的治疗。尽管有这些医疗干预措施，这五个- NSCLC患者的年生存率低于5%，突出了创新和更有效的治疗方法的必要性。 治疗NSCLC的策略。细胞周期蛋白依赖性激酶（CDK），如CDK 4和CDK 6的调节异常， 在70%的NSCLC患者中，并导致异常细胞增殖和肿瘤发生。帕博西尼（PD-03329， 商品名Ibrance）是第一个被批准用于乳腺癌的细胞周期蛋白依赖性激酶4和6抑制剂， 目前正在研究作为其他实体瘤（包括NSCLC）的单药治疗。虽然Palbociclib已经显示 复发性或转移性NSCLC II期临床试验中无进展生存期的初步改善 超过一半的患者会出现不良反应或出现耐药性和疾病进展 经过8周的治疗。Palbociclib通过将细胞阻滞在G1期达到治疗效果， 促进称为细胞衰老的不可逆的细胞周期停滞。衰老最初被认为 抑制肿瘤发生;然而，越来越多的证据表明，衰老细胞可以矛盾地 通过改变周围肿瘤微环境促进肿瘤发生和癌症复发。使用 促进合成致死性的衰老清除疗法可以绕过衰老的负面副作用， 通过驱动palbociclib处理的细胞凋亡，而不是 衰老通过基因筛选，我们确定了血栓调节蛋白（THBD），一种有效的抗凝剂 内皮受体，作为palbociclib诱导衰老的新的衰老清除靶点。THBD介导的信号传导 在palbociclib诱导的NSCLC癌细胞系衰老过程中上调， NSCLC细胞命运和存活的调节因子，因为抑制NSCLC细胞中的THBD信号转导减弱衰老 并促进细胞凋亡。重要的是，通过FDA批准的抑制THBD下游信号传导的活性， 在palbociclib治疗下，药物导致衰老的NSCLC细胞凋亡。基于这些发现，我们 提出了两个具体的目标，以充分研究THBD信号转导介导衰老的机制， palbociclib诱导的程序，并验证该途径作为诱导palbociclib合成致死性的靶点， 在体外和体内处理NSCLC细胞进行联合治疗，最终目标是开发 临床前和临床试验，以改善NSCLC患者的总体结局。

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases and is generally diagnosed at advanced stages, requiring multimodal therapy involving radiation, chemotherapy, and targeted therapies. Despite these medical interventions, the five- year survival rates of NSCLC patients are less than 5%, highlighting the need for innovative and more effective strategies to treat NSCLC. Dysregulation of cyclin-dependent kinases (CDKs), such as CDK4 and CDK6, occurs in 70% of NSCLC patients and results in aberrant cellular proliferation and tumorigenesis. Palbociclib (PD-03329, trade name Ibrance) is the first cyclin dependent kinase 4 and 6 inhibitor to be approved for breast cancer and is currently investigated as a monotherapy for other solid tumors, including NSCLC. While palbociclib has shown initial improvements in progression-free survival in a phase II clinical trial for recurrent or metastatic NSCLC patients, over half of patients either experience adverse effects or develop resistance and disease progression after eight weeks of treatment. Palbociclib achieves its therapeutic effect by arresting cells in G1 phase and promoting an irreversible cell cycle arrest known as cellular senescence. Senescence was initially thought to suppress tumorigenesis; however, growing evidence has suggested that senescent cells can paradoxically promote tumorigenesis and cancer relapse by altering the surrounding tumor microenvironment. The use of senolytic therapies to promote synthetic lethality may bypass the negative side effects of senescence and enhance the efficacy of palbociclib by either driving palbociclib-treated cells towards apoptosis rather than senescence. Through genetic screening, we identified thrombomodulin (THBD), a potent anticoagulant endothelial receptor, as a novel senolytic target for palbociclib-induced senescence. THBD-mediated signaling was upregulated during palbociclib-induced senescence in NSCLC cancer cell lines and served as a critical regulator of NSCLC cell fate and survival, as inhibition of THBD signaling in NSCLC cells attenuated senescence and promoted apoptosis. Importantly, inhibiting the activity of THBD downstream signaling by an FDA-approved drug caused senescent NSCLC cells to apoptose under treatment of palbociclib. Built on these findings, we propose two specific aims to fully investigate the mechanism by which THBD signaling mediates the senescent program induced by palbociclib and validate this pathway as a target to induce synthetic lethality in palbociclib- treated NSCLC cells both in vitro and in vivo for combinational therapy with the ultimate goal to develop preclinical and clinical trials to improve overall NSCLC patient outcome.