Abstract
Despite the recent implementation of immunotherapy as a single treatment or in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer (NSCLC), many patients do not benefit from this regimen due to primary treatment resistance or toxicity. Consequently, there is an urgent need to develop efficient biomarkers that can select patients who will benefit from immunotherapy thereby providing the appropriate treatment and avoiding toxicity. One of the biomarkers recently described for the stratification of NSCLC patients undergoing immunotherapy are mutations in STK11/LKB1, which are often associated with a lack of response to immunotherapy in some patients. Therefore, the purpose of this review is to describe the different cellular mechanisms associated with STK11/LKB1 mutations, which may explain the lack of response to immunotherapy. Moreover the review addresses the co-occurrence of additional mutations that may influence the response to immunotherapy and the current clinical studies that have further explored STK11/LKB1 as a predictive biomarker. Additionally this work includes the opportunities and limitations to look for the STK11/LKB1 status in the therapeutic strategy for NSCLC patients.
Highlights
Over the past few years, the mortality due to non-small cell lung cancer (NSCLC)decreased significantly, mainly due to early diagnosis, and to the development of new therapeutic strategies, including targeted therapies [1]
KEAP1 conferred chemoresistance in preclinical models of lung adenocarcinoma and that patients with late stage NSCLC with KEAP1/NFE2L2/CUL3 mutations had a shorter time to treatment failure and overall survival when treated with front-line platinum doublet chemotherapy [121]
STK11 loss induced an increase in energetic/redox stress, which is tolerated, in part, through co-occurring KEAP1/NRF2-dependent metabolic adaptations, enhancing glutamine dependence, which rendered those tumors sensitive to glutaminase inhibitors [128]. This was further supported by new research using a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, which further confirmed that KEAP1 or NRF2-mutant cancers are dependent on increased glutaminolysis, which can be therapeutically exploited through the pharmacological inhibition of glutaminase [129]
Summary
Over the past few years, the mortality due to non-small cell lung cancer (NSCLC). decreased significantly, mainly due to early diagnosis, and to the development of new therapeutic strategies, including targeted therapies [1]. The introduction of immunotherapy alone or in combination with chemotherapy has had a dramatic impact on the prognosis of patients by providing a substantial improvement in overall survival [2] In this context, many clinical trials have evaluated immunotherapy in the first- and second-line settings with the aim to develop a more efficient treatment strategy with less toxicity [3,4,5,6,7,8,9,10,11]. Despite recent progress, the development and clinical validation of novel robust biomarkers that predict response, resistance and/or toxicity to the treatment in routine clinical care remain major challenges in thoracic oncology. This review aims to highlight the current research of STK11 mutations in late stage NSCLC, the considerations for its potential implementation in routine clinical care, and the current limitations of using the STK11 mutational status in decision making of the global therapeutic strategy in thoracic oncology
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
