Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University/King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
Clin Cancer Res. 2021 Mar 15;27(6):1720-1733. doi: 10.1158/1078-0432.CCR-20-2859. Epub 2020 Dec 15.
Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in /LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes.
We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type /LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain.
In stage III patients, with 4 years median follow-up, /LKB1 mutations were associated with higher LRR ( = 0.0108), and shorter DFS (HR 2.530, = 0.0029) and OS (HR 2.198, = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy.
These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.
放化疗是局部晚期非小细胞肺癌（NSCLC）的主要治疗方法，但目前尚无预测标志物可选择受益于这些治疗的患者。在这项研究中，我们研究了 NSCLC 中第二常见的肿瘤抑制因子/LKB1 的改变与放疗反应之间的关系，以及改善治疗效果的潜在治疗方法。
我们对 194 例 I-III 期 NSCLC 患者进行了回顾性分析，包括 164 例 III 期患者，这些患者携带突变或野生型/LKB1，接受放疗，并评估局部区域复发（LRR）、远处转移率、无病生存率（DFS）和总生存率（OS），我们还使用 LKB1 缺失或获得的 NSCLC 细胞系的同源对，研究了 LKB1 在介导放疗抵抗中的因果作用。
在 III 期患者中，中位随访 4 年，/LKB1 突变与更高的 LRR（=0.0108）、较短的 DFS（HR 2.530，=0.0029）和 OS（HR 2.198，=0.0263）相关。LKB1 缺失促进了对放疗的相对抵抗，这依赖于 KEAP1/NRF2 通路来维持氧化还原平衡。通过 KEAP1 表达抑制 KEAP1/NRF2 通路，或药理学抑制谷氨酰胺酶（GLS）1，可使 LKB1 缺失的肿瘤对放疗敏感。
这些数据提供了证据，表明 LKB1 缺失与 NSCLC 患者接受放疗后的 LRR 和不良临床结局相关，靶向 KEAP1/NRF2 通路或 GLS 抑制可能是使 LKB1 缺失的肿瘤对放疗敏感的潜在方法。
