Knetki-Wróblewska Magdalena, Wojas-Krawczyk Kamila, Krawczyk Paweł, Krzakowski Maciej
Lung Cancer and Chest Tumours Department, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
Pneumonology, Oncology and Allergology Department, Medical University in Lublin, Lublin, Poland.
Transl Lung Cancer Res. 2024 Dec 31;13(12):3718-3730. doi: 10.21037/tlcr-24-552. Epub 2024 Dec 23.
Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (), Kelch-like ECH-associated protein 1 () and Kirsten rat sarcoma viral oncogene homolog () among them. The gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of or abnormalities with the mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of and genes mutations with the gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with -, - and -mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.
免疫检查点抑制剂（ICIs）已成为晚期非小细胞肺癌（NSCLC）患者的既定治疗选择。然而，单药免疫疗法以及与化疗联合使用的疗效似乎取决于某些基因中分子异常的存在，其中包括丝氨酸/苏氨酸激酶11（STK11）、 Kelch样ECH相关蛋白1（KEAP1）和 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）。STK11基因是细胞对氧化应激和亲电应激反应的关键调节因子，因此在维持细胞稳态中起关键作用。STK11基因编码一种丝氨酸/苏氨酸激酶（STK11），参与细胞生长、极性、运动性、分化和细胞代谢的调节。STK11基因突变通常与免疫“冷”肿瘤微环境相关。与单独出现时相比，STK11或KEAP1异常与KRAS突变同时出现会改变肿瘤微环境的组成。基于临床试验回顾性分析的当前数据表明，在晚期NSCLC患者中，无论治疗方法如何，STK11和KEAP1基因突变与KRAS基因突变同时存在对预后有负面影响。然而，这组患者不应被忽视，因为他们在晚期NSCLC患者中占相当大的比例。针对两种ICIs [抗程序性死亡1（PD-1）/抗细胞毒性T淋巴细胞抗原4（CTLA-4）]联合化疗的免疫疗法，在这组患者中可能比单独的免疫疗法或化疗更有效。现有临床研究结果可证实这一论点。在此，我们总结了联合免疫疗法治疗STK11、KEAP1和KRAS基因突变患者的理论依据以及临床试验结果。当然，有必要开展一项前瞻性临床试验，以评估联合免疫疗法在上述患者群体中的有效性。
