HSPA5 and FGFR1 genes in the mesenchymal subtype of glioblastoma can improve a treatment efficacy.

Tyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

Endomucin selectively regulates vascular endothelial growth factor receptor-2 endocytosis through its interaction with AP2.

The endothelial glycocalyx, located at the luminal surface of the endothelium, plays an important role in the regulation of leukocyte adhesion, vascular permeability, and vascular homeostasis. Endomucin (EMCN), a component of the endothelial glycocalyx, is a mucin-like transmembrane glycoprotein selectively expressed by venous and capillary endothelium. We have previously shown that knockdown of EMCN impairs retinal vascular development in vivo and vascular endothelial growth factor 165 isoform (VEGF165)-induced cell migration, proliferation, and tube formation by human retinal endothelial cells in vitro and that EMCN is essential for VEGF165-stimulated clathrin-mediated endocytosis and signaling of VEGF receptor 2 (VEGFR2). Clathrin-mediated endocytosis is an essential step in receptor signaling and is of paramount importance for a number of receptors for growth factors involved in angiogenesis. In this study, we further investigated the molecular mechanism underlying EMCN's involvement in the regulation of VEGF-induced endocytosis. In addition, we examined the specificity of EMCN's role in angiogenesis-related cell surface receptor tyrosine kinase endocytosis and signaling. We identified that EMCN interacts with AP2 complex, which is essential for clathrin-mediated endocytosis. Lack of EMCN did not affect clathrin recruitment to the AP2 complex following VEGF stimulation, but it is necessary for the interaction between VEGFR2 and the AP2 complex during endocytosis. EMCN does not inhibit VEGFR1 and FGFR1 internalization or their downstream activities since EMCN interacts with VEGFR2 but not VEGFR1 or FGFR1. Additionally, EMCN also regulates VEGF121-induced VEGFR2 phosphorylation and internalization.

Predictive insights into plant-based compounds as fibroblast growth factor receptor 1 inhibitors: a combined molecular docking and dynamics simulation study.

The discovery of novel therapeutic agents with potent anticancer activity remains a critical challenge in drug development. Natural products, particularly bioactive phytoconstituents derived from plants, have emerged as promising sources for anticancer drug discovery. In this study, we used virtual screening techniques to explore the potential of bioactive phytoconstituents as inhibitors of fibroblast growth factor receptor 1 (FGFR1), a key signaling protein implicated in cancer progression. We used virtual screening techniques to analyze phytoconstituents extracted from the IMPPAT 2.0 database. Our primary objective was to discover promising inhibitors of FGFR1. To ensure the selection of promising candidates, we initially filtered the molecules based on their physicochemical properties. Subsequently, we performed binding affinity calculations, PAINS, ADMET, and PASS filters to identify nontoxic and highly effective hits. Through this screening process, one phytocompound, namely Mundulone, emerged as a potential lead. This compound demonstrated an appreciable affinity for FGFR1 and exhibited specific interactions with the ATP-binding site residues. To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics. These analyses provided valuable information regarding the dynamic behavior and stability of the compounds in complexes with FGFR1. Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field.Communicated by Ramaswamy H. Sarma.

Phosphate-sensing mechanisms and functions of phosphate as a first messenger.

Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human body, and around 85% of phosphate is present in bone as a constituent of hydroxyapatite, Ca10(PO4)6(OH)2. Because hypophosphatemia induces rickets/osteomalacia, and hyperphosphatemia results in ectopic calcification, blood phosphate (inorganic form) level must be regulated in a narrow range (2.5 mg/dL to 4.5 me/dL in adults). However, as yet it is unknown how bone senses changes in blood phosphate level, and how bone regulates the production of FGF23. Our previous data indicated that high extracellular phosphate phosphorylates FGF receptor 1 (FGFR1) in an unliganded manner, and its downstream intracellular signaling pathway regulates the expression of GALNT3. Furthermore, the post-translational modification of FGF23 protein via a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production due to high dietary phosphate. Therefore, our research group proposes that FGFR1 works as a phosphate-sensing receptor at least in the regulation of FGF23 production and blood phosphate level, and phosphate behaves as a first messenger. Phosphate is involved in various effects, such as stimulation of parathyroid hormone (PTH) synthesis, vascular calcification, and renal dysfunction. Several of these responses to phosphate are considered as phosphate toxicity. However, it is not clear whether FGFR1 is involved in these responses to phosphate. The elucidation of phosphate-sensing mechanisms may lead to the identification of treatment strategies for patients with abnormal phosphate metabolism.

Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely. METHODS: Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations. RESULTS: Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity. CONCLUSION: FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.

The pathophysiology of hypophosphatemia.

After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including "ectopic FGF23 syndrome," "alcohol consumption-induced FGF23-related hypophosphatemia," "anti-mitochondrial antibody associated hypophosphatemia," and "vitamin D-dependent rickets type 3." Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced.

The Comparison of Commercial Serum-Free Media for Hanwoo Satellite Cell Proliferation and the Role of Fibroblast Growth Factor 2.

Fetal bovine serum (FBS), which contains various nutrients, comprises 20% of the growth medium for cell-cultivated meat. However, ethical, cost, and scientific issues, necesitates identification of alternatives. In this study, we investigated commercially manufactured serum-free media capable of culturing Hanwoo satellite cells (HWSCs) to identify constituent proliferation enhancing factors. Six different serum-free media were selected, and the HWSC proliferation rates in these serum-free media were compared with that of control medium supplemented with 20% FBS. Among the six media, cell proliferation rates were higher only in StemFlexTM Medium (SF) and Mesenchymal Stem Cell Growth Medium DXF (MS) than in the control medium. SF and MS contain high fibroblast growth factor 2 (FGF2) concentrations, and we found upregulated FGF2 protein expression in cells cultured in SF or MS. Activation of the fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathway and stimulation of muscle satellite cell proliferation-related factors were confirmed by the presence of related biomarkers (FGFR1, FRS2, Raf1, ERK, p38, Pax7, and MyoD) as indicated by quantitative polymerase chain reaction, western blotting, and immunocytochemistry. Moreover, PD173074, an FGFR1 inhibitor suppressed cell proliferation in SF and MS and downregulated related biomarkers (FGFR1, FRS2, Raf1, and ERK). The promotion of cell proliferation in SF and MS was therefore attributed to FGF2, which indicates that FGFR1 activation in muscle satellite cells may be a target for improving the efficiency of cell-cultivated meat production.

NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1.

Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.

FGFR1Pred: an artificial intelligence-based model for predicting fibroblast growth factor receptor 1 inhibitor.

Fibroblast growth factor receptors (FGFRs) are a family of cell surface receptors that bind to fibroblast growth factor (FGF) and mediate various cellular functions (translocating proteins, tissue repair, cell proliferation, development, and differentiation) through complex signaling pathways. The FGFR1 growth receptor is essential in the pathogenesis of numerous malignancies, including but not limited to breast cancer, bladder cancer, hepatocellular carcinoma (HCC), and cholangiocarcinoma. The higher levels of FGFR1 expression on the surface of cancer cells cause overly active signaling, which leads to rapid cell proliferation, resulting in a high spread of cancer cells. The kinases that FGFR1 activates migrate across the cell nucleus, activating genes and kinase proteins necessary for the growth and survival of cancerous cells. Therefore, FGFR1 targeting shows therapeutic promise in some diseases, including cancer. Inhibitors of FGFR1s are being developed and studied for their potential to block aberrant FGFR1 signaling and inhibit cancer growth. Since the discovery of new FGFR1 inhibitors in the laboratory is difficult, expensive, time-consuming, and labor-intensive, only a small number of FGFR1 inhibitors have been approved by the FDA for use in the treatment of cancer. To accelerate drug discovery by efficiently exploring the vast chemical space, and identifying potential candidates with higher accuracy and reduced cost, we developed artificial intelligence (AI)-based prediction models for FGFR1 inhibitors using a dataset of 2356 chemical compounds. Four machine learning (ML) algorithms (SVM, RF, k-NN, and ANN) were used to train different prediction models based on molecular descriptors (1D and 2D, with and without molecular fingerprints). Among all trained models, the random forest (RF)-based prediction model achieved the highest accuracy on the training (98.9%), test (89.8%), and external test (90.3%) datasets. The developed inhibitor prediction model (FGFR1Pred) provides a valuable tool for identifying potential FGFR1 inhibitors, expediting the drug discovery process and ultimately facilitating the development of new therapeutics. The model is made available at https://github.com/PGlab-NIPER/FGFR1Pred.git.

Infigratinib, a Selective Fibroblast Growth Factor Receptor Inhibitor, Suppresses Stent-Induced Tissue Hyperplasia in a Rat Esophageal Model.

PURPOSE: Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model. METHODS: Twenty-four male Sprague-Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations. RESULTS: All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05). CONCLUSIONS: Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model.

Fibroblast growth factor receptor 1 as a potential marker of terminal effector peripheral T helper cells in rheumatoid arthritis patients.

OBJECTIVES: RA is an autoimmune disease characterized by destructive polyarthritis. CD4+ T cells are pivotal to its pathogenesis, and our previous study revealed the expression of fibroblast growth factor receptor 1 (FGFR1) is modulated by MTX treatment in CD4+ T cells of RA patients; however, the roles of FGFR1 in CD4+ T cells in the pathogenesis of RA is unclear. Therefore, in this study, we aimed to characterize FGFR1-positive CD4+ T cells in RA patients. METHODS: The abundance of FGFR1-positive CD4+ T cells in peripheral blood and synovium was determined. Single-cell RNA sequencing (scRNA-seq) was performed on synovial CD4+ T cells to characterize FGFR1-positive cells. In addition, T cell activation status and cytokine production were determined using flow cytometry. RESULTS: The percentage of FGFR1-positive CD4+ T cells in the peripheral blood was higher in RA patients than in healthy controls (P =0.0035). They were also present in the synovium of active RA patients. The results of scRNA-seq revealed that peripheral Th (Tph) cells preferentially expressed FGFR1. Additionally, these FGFR1-positive Tph cells displayed a terminal effector cell phenotype. Consistent with this finding, FGFR1-positive CD4+ T cells in peripheral blood expressed IL-21 and IFN-γ. CONCLUSION: Our study provides evidence that FGFR1 marks terminal effector Tph cells in patients with RA.

Expression and clinical significance of FGFR1 and FGFR2 in laryngeal squamous cell carcinoma.

Background: Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor 2 (FGFR2) may be of significance in the development of laryngeal squamous cell carcinoma (SCC) tissues. Examination of the expression results of these factors may offer new insights into treatment of the disease, such as genetic and histological targeted target therapy. Methods: We selected tissue from 30 cases of laryngeal SCC, 23 cases of adjacent normal mucosa, and 26 cases of benign laryngeal mucosal tissues from patients who received surgery at the Otolaryngology Department of the Affiliated Hospital of Chengde Medical College between September 2020 and January 2022. The laryngeal cancers included nine cases of supraglottic, 20 glottic (vocal cord), and one case of subglottic cancer, while all benign laryngeal mucosal lesions were obtained from vocal cord polyps. The expression of FGFR1 and FGFR2 was detected in 30 laryngeal cancers, 23 adjacent normal mucosa, and 26 vocal cord polyps by immunohistochemical technology [immunohistochemistry (IHC)], and the correlation analysis of their expression in laryngeal cancer was performed. P<0.05 was represented statistically significant. Results: The expression of FGFR1 and FGFR2 was significantly different in laryngeal SCC and the normal tissue >0.5 cm from the tumor margin (P<0.05), and between laryngeal SCC and vocal polyps (P<0.05). There was no difference in FGFR1 and FGFR2 expression (P>0.05) between normal mucosal margins and vocal cord polyp tissue, and no correlation between FGFR1 and FGFR2 in laryngeal SCC and sex, age, smoking history, alcohol consumption history, tumor diameter, tumor lymph node metastasis, tumor differentiation degree, and Tumor-Node-Metastasis (TNM) stage (P>0.05), A moderate positive correlation between FGFR1 expression and FGFR2 expression in laryngeal SCC was seen (Rs=0.499, P<0.01). Conclusions: FGFR1 and FGFR2 may participate in the occurrence of SCC of the throat: (I) positive FGFR1 and FGFR2 expressions are not associated with gender, age, smoking history, alcohol consumption history, tumor diameter, lymph node metastasis, degree of differentiation, or TNM stage. (II) FGFR2 increases successively with higher FGFR1 expression and with a positive correlation in laryngeal SCC.

Fibroblast growth factor 10 attenuates chronic obstructive pulmonary disease by protecting against glycocalyx impairment and endothelial apoptosis.

BACKGROUND: The defects and imbalance in lung repair and structural maintenance contribute to the pathogenesis of chronic obstructive pulmonary diseases (COPD), yet the molecular mechanisms that regulate lung repair process are so far incompletely understood. We hypothesized that cigarette smoking causes glycocalyx impairment and endothelial apoptosis in COPD, which could be repaired by the stimulation of fibroblast growth factor 10 (FGF10)/FGF receptor 1 (FGFR1) signaling. METHODS: We used immunostaining (immunohistochemical [IHC] and immunofluorescence [IF]) and enzyme-linked immunosorbent assay (ELISA) to detect the levels of glycocalyx components and endothelial apoptosis in animal models and in patients with COPD. We used the murine emphysema model and in vitro studies to determine the protective and reparative role of FGF10/FGFR1. RESULTS: Exposure to cigarette smoke caused endothelial glycocalyx impairment and emphysematous changes in murine models and human specimens. Pretreatment of FGF10 attenuated the development of emphysema and the shedding of glycocalyx components induced by CSE in vivo. However, FGF10 did not attenuate the emphysema induced by endothelial-specific killing peptide CGSPGWVRC-GG-D(KLAKLAK)2. Mechanistically, FGF10 alleviated smoke-induced endothelial apoptosis and glycocalyx repair through FGFR1/ERK/SOX9/HS6ST1 signaling in vitro. FGF10 was shown to repair pulmonary glycocalyx injury and endothelial apoptosis, and attenuate smoke-induced COPD through FGFR1 signaling. CONCLUSIONS: Our results suggest that FGF10 may serve as a potential therapeutic strategy against COPD via endothelial repair and glycocalyx reconstitution.

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.

The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.

FGFR1/MAPK-directed brachyury activation drives PD-L1-mediated immune evasion to promote lung cancer progression.

Immune checkpoint inhibitors provide promising benefits for patients with cancer. However, efficacy has been encumbered by high resistance rates. It is critical to understand the basic mechanisms of tumor-mediated resistance to this treatment modality. Previous studies have found that the transcription factor brachyury is highly expressed in lung cancer. Here, we show that brachyury activation induces the upregulation of PD-L1 leading to inactivation of T cell proliferation in vitro and inhibited infiltration of CD8+ and CD3+ T cells into tumor in an immunocompetent mouse model. We further demonstrate that FGFR1/MAPK activation regulates brachyury and PD-L1 expressions and promotes immunosuppression. Blocking FGFR1/MAPK suppresses brachyury and PD-L1 expressions, revives immune activity, and reverses the resistance to anti-PD-1 treatment to produce a durable therapeutic response. We also find that lung cancer patients with high activation of the FGFR1-MAPK-brachyury-PD-L1 signature and low expression of CD8A, CD3D, or PDCD1 have worse survival outcomes. These findings elucidate a novel mechanism of immune escape from immune checkpoint therapy and provide an opportunity to enhance its therapeutic efficacy in the treatment of a subset of FGFR1/MAPK/brachyury/PD-L1-driven lung cancer.