The Importance of STK11/LKB1 Assessment in Non-Small Cell Lung Carcinomas

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.

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

“…A brief overview of the SKT11/AMPK axis LKB1 is a master kinase that serves as an "energy sensor" and plays a critical role in the conservation of ATP. This enzyme phosphorylates AMP-activated protein kinase (AMPK), which in turn promotes the production of ATP and inhibits the ATP-consuming processes [11]. In nutrient-scarce conditions, AMPK inhibits cell growth via the suppression of the mammalian target of the rapamycin (mTOR) pathway (Figure 1) [12].…”

“…The loss of LKB1 has also been observed to increase the production of S-adenosylmethionine (SAM), an important cofactor involved in deoxyribonucleic acid (DNA), RNA, and histone methylation [ 41 ]. This leads to the downregulation of stimulator of interferon genes (STING) and consequentially program death ligand 1 (PD-L1) [ 11 ]. Tumor cells with an abnormal STK11/LKB1 signaling axis were more likely to be surrounded by a “cold” immunosuppressive microenvironment characterized by the lack of inflammatory immune cells and the presence of multiple immunosuppressive cells (T-regulatory cells and tumor-associated neutrophils) [ 11 , 42 ].…”

Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective

“…The principal advantage of liquid biopsy is that it is minimally invasive and can be serially repeated to monitor disease evolution [48,51], including the development of resistance [2,52], the development of co-mutations [53], and for the more rapid detection of disease progression (i.e., ctDNA-defined progression) [54]. Liquid biopsies may be used for repeat biopsies at relapse [2], can reduce sampling error due to tumour heterogeneity [45], and are particularly useful when there is inadequate tumour tissue or when tumour tissue is inaccessible [52].…”

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…Other biomarkers are being studied and may join the list of genomic alterations for detection in different genes (such as STK11, KEAP1, mitogen-activated protein kinase (MEK), and phosphatidylinositol 3-kinase catalytic α (PI3KCA)) at diagnosis of advanced-stage NS-NSCLC (Table 1). In particular, some biomarkers may be useful in predicting positive (a high TMB) or negative responses (mutations in STK11 and KEAP1) to treatment with ICIs [312,313]. Certain mutations, such as those in STK11, can also open up new avenues of targeted therapies and may be detected with IHC [314,315].…”