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

摘要 肺癌是全世界与癌症相关的死亡最常见的原因。非小细胞肺癌(NSCLC) 占所有肺癌病例的85%，通常被诊断为晚期，需要多种模式 包括放射、化疗和靶向治疗在内的治疗。尽管有这些医疗干预，这五个人- 非小细胞肺癌患者的一年生存率不到5%，突显了创新和更有效的必要性 非小细胞肺癌的治疗策略。细胞周期蛋白依赖性激酶(CDKs)，如CDK4和CDK6的调节失调 在70%的非小细胞肺癌患者中，并导致细胞异常增殖和肿瘤形成。帕波西利(PD-03329， 商标：Ibrance)是第一个被批准用于乳腺癌和乳腺癌的细胞周期蛋白依赖性激酶4和6抑制剂 目前被研究为其他实体肿瘤的单一疗法，包括非小细胞肺癌。而Palbociclib已经展示了 复发或转移性非小细胞肺癌II期临床试验中无进展存活率的初步改善 患者，超过一半的患者要么经历不良反应，要么产生抵抗力和疾病进展 经过八周的治疗。Palbociclib通过将细胞阻滞在G1期和 促进一种称为细胞衰老的不可逆转的细胞周期停滞。衰老最初被认为是 抑制肿瘤的发生；然而，越来越多的证据表明，衰老的细胞可以矛盾地 通过改变周围的肿瘤微环境，促进肿瘤的发生和复发。对.的使用 促进合成致死性的衰老疗法可以绕过衰老和 通过促使帕波西利处理的细胞凋亡而不是 衰老。通过遗传筛选，我们鉴定出一种有效的抗凝血剂血栓调节蛋白(THBD) 血管内皮细胞受体，作为一种新的抗衰老靶点。THBD介导的信号转导 在帕波西利诱导的非小细胞肺癌细胞系衰老过程中上调，并作为关键的 非小细胞肺癌细胞命运和存活的调节因子，抑制THBD信号可延缓细胞衰老 并促进细胞凋亡。重要的是，通过FDA批准的一种药物抑制THBD下游信号的活性 药物诱导衰老的非小细胞肺癌细胞在帕波西利的作用下发生凋亡。基于这些发现，我们 提出两个具体目标，以充分研究THBD信号调节衰老的机制 程序，并验证该途径作为诱导Palbociclib合成致死性的靶点。 在体内和体外联合治疗NSCLC细胞，最终目标是发展 临床前和临床试验，以改善总体非小细胞肺癌患者的预后。

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.