非小细胞肺癌 (NSCLC) 中 STK11 和 KEAP1 的突变 (STK11MUT 和 KEAP1MUT) 频繁出现，并且通常与 KRAS 共同突变。多项研究表明 KRASMUT + STK11MUT 和 KRASMUT + KEAP1MUT 的共同发生与免疫检查点抑制剂 (ICI) 的反应降低以及对生存的负面影响有关。目前非常缺乏关于 STK11 + KEAP1 共突变或三重突变 (KRAS + STK11 + KEAP1) 的数据。最近 KRAS-G12C 抑制剂的可用性提高了 KRAS 突变 NSCLC 中这些共突变的临床相关性。我们提供了一项全面的生物信息学分析，涵盖了从 cBioPortal 检索到的六个数据集。不受治疗方式的影响，三重突变和 STK11MUT + KEAP1MUT 与总生存期 (OS) 显著减少相关。在各种治疗中，患有 KRAS G12C 三重突变的患者的 OS 显著减少，与仅患有 KRAS G12C 的患者相比。在 ICI 治疗下，患有 KRAS G12C 三重突变和仅患有 KRAS G12C 的患者的 OS 之间没有显著差异，但患有 KRAS 非 G12C 和 KRAS 非 G12C 三重突变的患者之间有显著差异。三重突变的原发肿瘤与仅 KRAS 突变的肿瘤相比，骨骼和肾上腺腺肿瘤的远处转移频率显著增加。此外，在携带三重突变的癌细胞系中进行的药物反应分析显示，WNT 通路抑制剂 XAV-939 是潜在的未来药物候选。与仅患有 KRASMUT 的患者相比，三重突变状态可能作为各种治疗中的负面预后和预测因子。KRAS G12C 通常似乎是 ICI 治疗的负面预测标志物。版权所有©2023 Elsevier B.V.。保留所有权利。

Mutations in STK11 (STK11MUT) and KEAP1 (KEAP1MUT) occur frequently in non-small cell lung cancer (NSCLC) and are often co-mutated with KRAS. Several studies linked the co-occurrence of KRASMUT + STK11MUT, as well as KRASMUT + KEAP1MUT to reduced response to immune checkpoint inhibitors (ICI) and even a negative impact on survival. Data focusing STK11 + KEAP1 co-mutations or the triple mutation (KRAS + STK11 + KEAP1) are scarce. The recent availability of KRAS-G12C inhibitors increases the clinical relevance of those co-mutations in KRAS-mutated NSCLC.We present a comprehensive bioinformatic analysis encompassing six datasets retrieved from cBioPortal.Independent of the treatment, triple mutations and STK11MUT + KEAP1MUT were significantly associated with a reduced overall survival (OS). Across treatments, OS of patients with a KRAS G12C triple mutation was significantly reduced compared to patients with KRAS G12C-only. Under ICI-therapy, there was no significant difference in OS between patients harboring the KRAS G12C-only and patients with the KRAS G12C triple mutation, but a significant difference between patients harboring KRAS non-G12C and KRAS non-G12C triple mutations. Triple mutated primary tumors showed a significantly increased frequency of distant metastases to bone and adrenal glands compared to KRAS-only mutated tumors. Additionally, our drug response analysis in cancer cell lines harboring the triple mutations revealed the WNT pathway inhibitor XAV-939 as a potential future drug candidate for this mutational situation.The triple mutation status may serve as a negative prognostic and predictive factor across treatments compared to KRASMUT-only. KRAS G12C generally seems to be a negative predictive marker for ICI-therapy.Copyright © 2023 Elsevier B.V. All rights reserved.