Biological insights in non-small cell lung cancer

Abstract

Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress. Several tumor types, including non-small cell lung cancer (NSCLC), upregulate the system xc- cystine/glutamate antiporter (xCT) through overexpression of the cystine transporter SLC7A11, thus sustaining intracellular cysteine levels to support glutathione synthesis. Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master regulator of oxidative stress resistance by regulating SLC7A11, whereas Kelch-like ECH-associated protein (KEAP1) acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2. Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC. Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress. Disruptions in cystine availability lead to iron-dependent lipid peroxidation, thus resulting in a type of cell death called ferroptosis. Pharmacologic inhibitors of xCT (either SLC7A11 or GPX4) induce ferroptosis of NSCLC cells and other tumor types. When cystine uptake is impaired, the intracellular cysteine pool can be sustained by the transsulfuration pathway, which is catalyzed by cystathionine-B-synthase (CBS) and cystathionine g-lyase (CSE). The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8+ T cell function and evasion of immunotherapy, diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions. Pyroptosis is a previously unrecognized form of regulated cell death. In NSCLCs driven by EGFR, ALK, or KRAS, selective inhibitors induce pyroptotic cell death as well as apoptosis. After targeted therapy, the mitochondrial intrinsic apoptotic pathway is activated, thus leading to the cleavage and activation of caspase-3. Consequently, gasdermin E is activated, thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis (indicated by characteristic cell membrane ballooning). Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.

Lanatoside C induces ferroptosis in non-small cell lung cancer in vivo and in vitro by regulating SLC7A11/GPX4 signaling pathway

“…The system xc − , a cystine/glutamate antiporter, is comprised of SLC7A11 and SLC3A2. SLC7A11, as a sodium-independent cystine-glutamate reverse transporter, is responsible for transporting extracellular cystine into the cell, which is then processed into cysteine, the rate-limiting substrate for GSH synthesis ( 29 , 30 ). A decrease in SLC7A11 may lead to a decrease in GSH, and the function of GPX4 is suppressed, contributing to the inhibition of SLC7A11/cysteine/GSH axis, ultimately triggering ferroptosis ( 31 ).…”

Different treatment modalities on the prognosis of patients with stage I–IIIa small cell lung cancer: a population based study

“…With recent advances in targeted therapy for lung cancer, the standard treatment for LS-SCLC is radiotherapy combined with chemotherapy ( 5 , 6 ). Although surgery has been largely abandoned as a treatment for patients with LS-SCLC, it can improve the prognosis of patients with stage I–IIA SCLC and stage IIB, and there is no significant difference in the 5-year survival rate between patients with stage I and stage II SCLC who receive surgery (63.8% vs. 65.5%) ( 7 - 14 ).…”