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.

Keywords: KRAS; STK11/LKB1; biomarker; immunotherapy; non-small cell lung carcinoma; targeted therapy.

Figure 1

The double-edged sword of liver kinase B1 (LKB1) in cancer cell metabolism. LKB1 is a master metabolic sensor that acts as an energy gauge to sustain cancer cell survival. Upon nutrient deprivation within the center of large tumors, LKB1 reprograms cell metabolism by slowing down all ATP-consuming processes while simultaneously stimulating ATP-generating processes. By organizing this overall stress response, LKB1 may adapt cancer cell growth under conditions of energy shortage.

Figure 2

Loss of LKB1 drives the tumor immune escape. The loss of LKB1, the second most commonly altered tumor suppressor in NSCLC, promotes the production of SAM, a substrate for the DNA and histone methyltransferases DNMT1, EZH2 and other epigenetic silencing enzymes. This downregulates the expression of STING, impairing dsDNA sensing, and thereby the expression of immune checkpoint regulating proteins like PD-L1 and T cell chemokines. Therefore, the LKB1-deficient tumors are characterized by a so-called “cold” immunosuppressive tumor microenvironment (blue), which shows the striking infiltration of immunosuppressive cells (TAN; tumor-associated neutrophil; Treg, T lymphocyte regulator, blue) and the exclusion of inflamed immune cells (CD8 T cells, NK, CD4 T cells and M1; Macrophage type 1, red). Epigenetic therapies that reactivate LKB1 or the STING pathway may boost an anticancer immune response in LKB1-deficient cancers with the resistance to immune-checkpoint blockade (ICI, immune checkpoint inhibitor).