Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.

IF 4 2区 医学 Q2 ONCOLOGY Translational lung cancer research Pub Date : 2024-12-31 Epub Date: 2024-12-23 DOI:10.21037/tlcr-24-552
Magdalena Knetki-Wróblewska, Kamila Wojas-Krawczyk, Paweł Krawczyk, Maciej Krzakowski
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Abstract

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 (STK11), Kelch-like ECH-associated protein 1 (KEAP1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) among them. The KEAP1 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 STK11 gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The STK11 gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of STK11 or KEAP1 abnormalities with the KRAS 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 STK11 and KEAP1 genes mutations with the KRAS 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 STK11-, KEAP1- and KRAS-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.

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STK11, KEAP1和KRAS突变的新见解:对晚期非小细胞肺癌患者免疫治疗的影响
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,单药免疫治疗以及联合化疗的疗效似乎依赖于某些基因的分子异常存在,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)。KEAP1基因是细胞对氧化应激和亲电应激反应的关键调控因子,因此在维持细胞稳态中起着关键作用。STK11基因编码丝氨酸/苏氨酸激酶(STK11),参与调节细胞生长、极性、运动、分化和细胞代谢。STK11基因突变通常与免疫“冷”肿瘤微环境有关。与单独出现时相比,STK11或KEAP1异常与KRAS突变的共同出现改变了肿瘤微环境的组成。目前基于临床试验回顾性分析的数据表明,无论采用何种治疗方法,晚期NSCLC患者STK11、KEAP1基因突变与KRAS基因突变共存都会对预后产生负面影响。然而,这组患者不应该被忽略,因为他们占晚期NSCLC患者的很大比例。在该组患者中,以抗程序性死亡1 (PD-1)/抗细胞毒性t淋巴细胞抗原4 (CTLA-4)两种ICIs为重点的免疫治疗联合化疗可能比单独免疫治疗或化疗更有效。现有的临床研究结果证实了这一论点。在此,我们总结了STK11-、KEAP1-和kras突变基因患者联合免疫治疗的理论依据和临床试验结果。当然,有必要建立一个前瞻性临床试验,以评估联合免疫治疗在上述患者组中的有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
2.50%
发文量
137
期刊介绍: Translational Lung Cancer Research(TLCR, Transl Lung Cancer Res, Print ISSN 2218-6751; Online ISSN 2226-4477) is an international, peer-reviewed, open-access journal, which was founded in March 2012. TLCR is indexed by PubMed/PubMed Central and the Chemical Abstracts Service (CAS) Databases. It is published quarterly the first year, and published bimonthly since February 2013. It provides practical up-to-date information on prevention, early detection, diagnosis, and treatment of lung cancer. Specific areas of its interest include, but not limited to, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to lung cancer.
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