Lung squamous cell carcinoma (LUSC) is a non-small cell lung cancer and is the second most frequent subtype of lung cancer, the main cause of cancer deaths worldwide, often resulting in a late-stage incurable disease (1). Cigarette smoking is the main risk factor associated with preinvasive lesions observed in LUSC. Five molecular subtypes have been recently identified after the characterization of the proteogenomic landscape of LUSC (2). Yet few therapies exist, and the exploration of new potential molecular targets is needed. Many genes present in the network have a known association with LUSC as represented in the QKG. Immune checkpoint inhibitors targeting some of these (CD274, PDCD1) have resulted in increased overall survival and progression-free survival in patients with metastatic LUSC when combined with chemotherapy (QKG, 3). Other players (amplifications in FGFR1 and PIK3CA, and deletions in CDKN2A) represent known molecular pathways and therapeutics have been tested in clinical trials (QKG, 3). Significantly mutated genes are present such as TP53 (the most frequently mutated gene in LUSC), or FBXW7 (F-box-type ubiquitin ligase, which targets several oncoproteins for degradation) as well as members of the EGFR family (EGFR, ERRB2, ERRB3 and ERRB4) involved in key biological processes (cell survival, growth, proliferation, and differentiation), and members of the tubulin family (TUB4A, TUBG1) involved in cell cycle progression. For these genes, either FDA-approved treatments for symptomatic or asymptomatic progressing advanced or metastatic LUSC have been already approved or clinical trials are ongoing (QKG). Other genes involved in angiogenesis, such as KDR, may be beneficial for treating LUSC (4), while inactivation of 2 ligand-dependent nuclear receptors (NR1H2, NR1H3) involved in cholesterol metabolism spontaneously leads to LUSC in a mouse model (5). Finally association of NCOA6 (involved in the hormone-dependent coactivation of several receptors), RNF5 (cell motility), TNK2 (cell proliferation, migration, invasion) have been observed with LUSC (COSMIC).

The network contains an additional 35 genes predicted to be associated with LUSC: ARRDC3, COX7A2, CYFIP2, DAP3, DNAJA4, FABP1, FBXL7, FGF21, FOXP4, GAS1, GCKR, GPC6, HADHB, HNF4A, HSD17B4, IRS2, KPNB1, LONP1, MARCHF6, MEOX2, MRPL12, MTNR1A, MTNR1B, NUDT6, NUP153, PAPOLA, PDZK1, RBBP4, REN, SLC16A10, SLC25A5, TWNK, UHRF1BP1, VWA8, ZNF687. None of these currently have known connections with LUSC directly in our QKG. However, many have direct or indirect molecular connections with some aspect of cancer progression or metastasis. A few examples are discussed briefly below.

Multiomic analysis has recently identified SLC25A5 as a potential driver gene in cervical cancer (6) and could serve as a prognostic marker in colon cancer (7). SLC25A5 is a mitochondrial solute carrier, it is connected to previously described actors in LUSC (CDKN2A, ERRB3, TUBG1, TP53) but also to predicted ones in our network (HFN4A, DNAJA4). HNF4a itself has been shown to be a marker for invasive mucinous lung adenocarcinoma (another subtype of NSCLC) (8). DNAJA4 was shown to be a metastasis suppressor via APOE in melanoma (9). Similarly, mitochondrial COX7A2 (involved in oxidative phosphorylation) is connected to three important transcription regulators (TP53, HNF4A and MEOX2). MEOX2 is involved in chemoresistance to EGFR-Tyrosine Kinase inhibitor therapy in lung cancer cells (10). Fibroblast Growth Factors are known to promote tumor growth and angiogenesis in solid tumors, the predicted FGF2 in the network is known to activate FGFR1 (QKG). Interestingly FGF21 is thought to be a promoter of lung cancer and a potential therapeutic target (11). HSD17B4, a multifunctional enzyme localized in peroxisomes involved in the beta-oxidation pathway for long fatty acids is downregulated in NSCLC (12), highlighting its potential anti-tumor activity in lung cancer (13). Finally, a study screening TCGA samples highlighted that RNF687 is highly expressed in lung adenocarcinoma and correlates with poor survival (14).

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