Search Results (1,130)

Background: Colorectal cancer is the third most diagnosed cancer and a leading cause of cancer-related deaths worldwide. Early detection significantly improves patient outcomes, yet many cases are identified only at late stages. The high molecular and genetic heterogeneity of colorectal cancer presents major challenges in accurate diagnosis, prognosis, and therapeutic stratification. Recent advances in gene expression profiling offer new opportunities to discover genes that play a role in colorectal cancer carcinogenesis and may contribute to early diagnosis, prognosis prediction, and the identification of novel therapeutic targets. Methods: This study involved 142 samples: 84 primary tumor samples, 27 liver metastases, and 31 adjacent non-tumor tissues serving as controls. RNA sequencing was performed on a subset of tissues (12 liver metastases and 3 adjacent non-tumor tissues) using a targeted RNA panel covering 395 cancer-related genes. Data processing and differential gene expression analysis were carried out using the DRAGEN RNA and DRAGEN Differential Expression tools. The expression of six genes involved in hypoxia and epithelial-to-mesenchymal transition (EMT) pathways (SLC16A3, ANXA2, P4HA1, SPP1, KRT19, and LGALS3) identified as significantly differentially expressed was validated across the whole cohort via quantitative real-time PCR. The relative expression levels were determined using the ΔΔct method and log2FC, and compared between different groups based on the sample type; clinical parameters; and mutational status of the genes KRAS, PIK3CA, APC, SMAD4, and TP53. Results: Our results suggest that the expression of all the validated genes is significantly altered in metastases compared to non-tumor control samples (p < 0.05). The most pronounced change occurred for the genes P4HA1 and SPP1, whose expression was significantly increased in metastases compared to non-tumor and primary tumor samples, as well as between clinical stages of CRC (p < 0.001). Furthermore, all genes, except for LGALS3, exhibited significantly altered expression between non-tumor samples and samples in stage I of the disease, suggesting that they play a role in the early stages of carcinogenesis (p < 0.05). Additionally, the results suggest the mutational status of the KRAS gene did not significantly affect the expression of any of the validated genes, indicating that these genes are not involved in the carcinogenesis of KRAS-mutated CRC. Conclusions: Based on our results, the genes P4HA1 and SPP1 appear to play a role in the progression and metastasis of colorectal cancer and are candidate genes for further investigation as potential biomarkers in CRC. Full article

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. Full article

Background: Wide application of genome sequencing technologies has highlighted extensive genetic diversity in Acute Myeloid Leukemia (AML), yet the specific roles of individual genes remain unclear. This systematic review and meta-analysis aims to provide robust evidence for the prognostic impact of somatic gene mutations in de novo AML patients, while also exploring the prevalence of these mutations. Methods: Eligible studies were identified from PubMed and Scopus, with a focus on those reporting the prognostic influence of somatic gene mutations on overall survival (OS) or relapse-free survival (RFS) when compared to wild-type carriers. We calculated the pooled prevalence with 95% confidence intervals to assess the frequency of these mutations, and the pooled Hazard Ratio (HR) to compare OS and RFS associated with specific gene mutations. Results: We evaluated 53 somatic gene mutations using 80 studies, involving 20,048 de novo AML patients. The analysis revealed that the most prevalent affected genes were NPM1 (27%), DNMT3A (26%), and FLT3-ITD (24%). Mutations in CSF3R, TET2, and TP53 were significantly associated with poorer OS or RFS (p < 0.05). Sensitivity analysis confirmed that ASXL1, DNMT3A, and RUNX1 mutations were consistently linked to inferior OS or RFS. In contrast, CEBPAdm mutations were associated with favorable OS [HR = 0.39 (0.30–0.50)] and RFS [HR = 0.44 (0.37–0.54)]. Subgroup analysis showed that FLT3-ITD mutations were consistently associated with worse OS or RFS across all subgroups, though no significant subgroup differences were noted. No significant impact on OS or RFS was observed for mutations in GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. Conclusions: These findings provide critical insights into AML prognosis, aiding clinical decision-making and improving risk stratification strategies. Full article

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype. However, the prognostic relevance of KRAS G12C compared with non-G12C mutations in patients receiving immune checkpoint inhibitors (ICIs) remains unclear. Methods: We retrospectively analyzed 80 NSCLC patients treated with ICIs between January 2020 and July 2024; data were censored on 3 July 2025. The cohort included 32 KRAS-mutant (20 G12C, 12 non-G12C) and 48 KRAS wild-type patients. Clinicopathological features, treatment details, and survival outcomes were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, with group comparisons made using the log-rank test. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors. Results: Among 80 NSCLC patients treated with ICIs, the median OS and PFS were 14.3 and 8.2 months, respectively. Survival outcomes were comparable between KRAS-mutant and wild-type patients. Within the KRAS-mutant subgroup (n = 32), baseline characteristics were generally balanced between G12C (n = 20) and non-G12C (n = 12) cases, with non-significant trends toward higher metastatic burden and PD-L1 ≥ 50% in the G12C group. Median OS was significantly longer in G12C patients than in non-G12C patients (20.7 vs. 6.4 months; p = 0.021), whereas PFS did not differ significantly (10.2 vs. 3.7 months; p = 0.181). In multivariate analysis, non-G12C mutation independently predicted increased mortality risk (HR 3.35, 95% CI 1.26–8.89; p = 0.015). For PFS, recurrent disease status was associated with improved outcomes in univariate analysis (HR 0.30, 95% CI 0.09–0.94; p = 0.040), but no independent predictors were identified in multivariate modeling. Conclusions: In NSCLC patients treated with ICIs, the KRAS G12C mutation was associated with significantly improved OS compared with other KRAS subtypes, independent of clinicopathological characteristics. These findings suggest distinct biological behavior of KRAS variants in immunotherapy response and warrant further prospective validation. Full article

Background/Objectives: Next-Generation Sequencing (NGS) has transformed cancer diagnostics and treatment by enabling comprehensive genomic profiling of tumors. This review aims to summarize the current applications of NGS in oncology, highlighting its role in early detection, precision therapy, and disease monitoring. Methods: We conducted a comprehensive review of the recent literature, focusing on the application of NGS in cancer care. Results: NGS enables high-resolution genomic profiling, identifying actionable mutations (e.g., EGFR, KRAS, and ALK) and immunotherapy biomarkers (e.g., PD-L1, TMB, and MSI), guiding personalized treatment selection and improving outcomes in advanced malignancies. Liquid biopsy enhances diagnostic accessibility and enables real-time monitoring of minimal residual disease and treatment resistance. Despite these advances, widespread clinical adoption remains constrained by technical limitations (e.g., coverage uniformity and sample quality), economic challenges (high costs and complex reimbursement), and interpretative issues, including the management of variants of uncertain significance (VUSs). Conclusions: NGS is central to precision oncology, enabling molecularly driven cancer care. Integration with artificial intelligence, single-cell sequencing, spatial transcriptomics, multi-omics, and nanotechnology promises to overcome current limitations, advancing personalized treatment strategies. Standardization of workflows, cost reduction, and improved bioinformatics expertise are critical for its full clinical integration. Full article

Colorectal cancer (CRC) is driven by a complex spectrum of somatic mutations and structural variants that contribute to tumor heterogeneity and therapy resistance. In this study, we performed a comparative analysis of short-read Illumina and long-read Nanopore sequencing technologies across multiple CRC sample groups, encompassing diverse tissue morphologies. Our evaluation included general base-level metrics—such as nucleotide ratios, sequence match rates, and coverage—as well as variant calling performance, including variant allele frequency (VAF) distributions and pathogenic mutation detection rates. Focusing on clinically relevant genes (KRAS, BRAF, TP53, APC, PIK3CA, and others), we characterized platform-specific detection profiles and completed the ground truth validation of somatic KRAS and BRAF mutations. Structural variant (SV) analysis revealed Nanopore’s enhanced ability to resolve large and complex rearrangements, with consistently high precision across SV types, though recall varied by variant class and size. To enable direct comparison with the Illumina exome panel, we applied an exonic position reference file. To assess the impact of depth and PCR amplification, we completed an additional high-coverage Nanopore sequencing run. This analysis confirmed that PCR-free protocols preserve methylation signals more accurately, reinforcing Nanopore’s utility for integrated genomic and epigenomic profiling. Together, these findings underscore the complementary strengths of short- and long-read sequencing platforms in high-resolution cancer genomics, and we highlight the importance of coverage normalization, epigenetic fidelity, and rigorous benchmarking in variant discovery. Full article

Blocking the MAPK pathway is a strategy to stop cancer cells proliferation. Despite all the successes, the acquisition of drug resistance by cells, as well as the mutational status of the downstream protein KRAS, reduces the tumor response to therapy. Ribonuclease binase from Bacillus pumilus is among the agents that block this pathway through direct interaction with EGFR and RAS. The present study is aimed at the design, optimization, and characterization of a novel complex based on antitumor binase immobilized on microgranular clinoptilolite-containing rock to ensure its prolonged release in the gastrointestinal tract. A set of modern methods including transmission electron microscopy, scanning electron microscopy, and computed tomography was used to characterize the granularity, porosity and elemental composition of the carrier. The size of binase particles, measured by atomic force microscopy at 7 nm, allows enzyme penetration into meso- and macropores of the carrier. Calorimetric results confirm that binase is stable at high temperatures, even exceeding those in the body, and retains catalytic activity in the model fluids of the gastrointestinal tract. The parameters for processing a natural clinoptilolite-containing rock and the conditions for binase sorption were selected. The gradual release of the enzyme from the carrier lasts over 20 h, which provides cytotoxicity towards human adenocarcinoma cells during movement through the gastrointestinal tract. Thus, for the first time a promising long-acting complex with antitumor and detoxifying properties was successfully created. Full article

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use. Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne^® CDx (F1; n = 5019) and FoundationOne^® Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H, FGFR2/RET/NTRK fusions, BRAF V600E, KRAS G12C, IDH1 mutations, and ERBB2 amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne^® Liquid). Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75; p < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90; p = 0.01) and ERBB2 amplification (OR 0.42, 0.31–0.57; p < 0.001), with no significant differences for MSI-H, IDH1, KRAS G12C, or BRAF V600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors. Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate. Full article

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide. Recent advances in next-generation sequencing have revealed a variety of genomic alterations―such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―that may serve as therapeutic targets. However, the influence of underlying etiologic factors, including chronic liver and biliary diseases, on the molecular landscape of CCA remains unclear. Objective: This review aimed to synthesize the current knowledge on the genomic and molecular alterations of CCA in the context of diverse etiologic factors, including hepatitis B virus, hepatitis C virus, primary sclerosing cholangitis (PSC), primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and liver fluke infection. Main findings: Certain backgrounds, such as PSC and liver fluke infection, are associated with distinct molecular signatures (e.g., TP53, SMAD4, KRAS, and ERBB2 alterations), whereas others, such as MASLD or ALD, show limited and inconsistent genomic data. Targetable alterations―including FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―are heterogeneously distributed across etiologies and anatomical subtypes. Molecular targeted therapies such as FGFR and IDH1 inhibitors have shown clinical benefits in selected patients. Conclusions: A better understanding of how chronic liver and biliary diseases shape the genomic landscape of CCA will inform the development of personalized treatments, surveillance strategies, and preventive approaches. Large-scale etiology-stratified genomic studies integrating multiomics and real-world clinical data are urgently needed to advance precision oncology in CCA. Full article

Molecular profiling of testicular germ cell tumors (TGCTs) provides critical insights into personalized treatment approaches, particularly for patients with recurrent or treatment-resistant disease. In this study, we retrospectively analyzed clinicopathological and targeted genomic sequencing data from 27 TGCT patients, including 7 seminomas, 19 non-seminomas, and 1 prepubertal type teratoma, across stage I (48%), stage II (41%), and stage III (11%). Tumor samples were obtained from 27 orchiectomies, with additional pathological specimens collected from 16 of these patients during retroperitoneal lymph node dissections (RPLNDs); these included 8 chemotherapy-naïve and 8 post-chemotherapy cases. The median tumor mutational burden (TMB) was 0.5 mutations/Mb, consistent with the low mutation rate typically observed in TGCTs. Somatic mutations and copy number gain alterations were detected in 56% (15/27) of patients, primarily in KRAS (25.9%), KIT (11.1%), and PIK3CB (7.4%). PD-L1 positive immunoreactivity by immunohistochemistry was observed in 75% of tumors (60% in stage I, 100% in stage III) analyzed (n = 8), suggesting potential immune checkpoint inhibitor applicability in advanced disease. Microsatellite instability (MSI) status was identified in 23 tumors; all were classified as MSI-low, supporting the rarity of MSI-driven tumorigenesis in TGCTs. Actionable gene alterations linked to FDA-approved therapies, interventional therapies, and clinical trials in TGCTs and other cancers (lung, skin, colon, liver, stomach, and breast) were present in 59.3% (16/27) of patients, indicating potential therapeutic repurposing. Additionally, germline variants of uncertain clinical significance in known cancer actionable genes, including MSH2, MSH6, RB1, and BRCA2, were found in 9 patients, warranting further investigation regarding their clinical relevance and susceptibility risk. Our findings highlight that a substantial proportion of TGCT patients harbor potentially actionable molecular alterations across all disease stages. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

Introduction: Increasingly, identification of BRAF mutation in colorectal cancer is used to guide management and predict cancer behaviour. There is, however, still significant diversity within this cohort of patients, both in terms of clinical phenotype and treatment outcomes. This may be explained, at least in part, by differences between classes of BRAF mutations and the presence of concomitant mutations. Methods: We present a retrospective cohort study of sequential patients diagnosed with BRAF-mutated (V600 and non-V600) colorectal cancer between 2014 and 2022. Information regarding presentation, treatment outcomes and molecular subtype was identified using the electronic medical record. Results: This study included 406 patients with BRAF-mutated colorectal cancer, 253 (228 ^V600BRAF) of whom had localised disease and 153 (137 ^V600BRAF) with metastatic disease at the time of diagnosis. In patients with localised disease at diagnosis, the ^V600BRAF mutation was associated with older median age (73 vs. 63 years, p = 0.04) and a higher prevalence of right-sided primary (73% vs. 40%, p < 0.01), mismatch repair deficiency (56% vs. 8%, p < 0.01), and faster time to disease relapse (p = 0.006). In the metastatic setting, ^non-V600BRAF mutation was associated with a higher prevalence of KRAS mutation (27% vs. 1%, p < 0.01), NRAS mutation (14% vs. 3%, p = 0.04) and PIK3CA mutation (33% vs. 8%, p = 0.02). Mismatch repair deficiency was more common in patients with ^V600BRAF mutations than in those with ^non-V600BRAF mutations (20% vs. 0%, p = 0.01). The median survival of patients with the ^V600BRAF mutation was 14 months, and 34 months in those with ^non-V600BRAF mutations. Concomitant RNF43 mutation in metastatic disease, was associated with a significantly higher incidence of disease control from combined BRAF and EGFR inhibition, when compared to those without an RNF43 mutation (100% vs. 54%, p = 0.02). Conclusions: Presentation and outcomes of BRAF-mutated colorectal cancer are heterogenous. The type of BRAF mutation, and the presence of concomitant RNF43 mutation, may explain some of the differences in cancer behaviour. Routine reporting of RNF43 mutations would assist clinicians to give more personalised treatment recommendations. Full article

Background: Centrosome amplification, a hallmark of cell cycle dysregulation, drives carcinogenesis through aneuploidy induction and invasive phenotype acquisition. In pancreatic adenocarcinoma—a malignancy characterized by profound genomic instability—the molecular circuitry of centrosome amplification remains enigmatic. Critical gaps persist in understanding its spatiotemporal dynamics in tumor microenvironment remodeling and therapy resistance. Methods: This study integrated centrosome amplification-related genes from TCGA and Genecards, established a prognostic risk model through univariate Cox regression–LASSO penalized Cox regression–multivariate Cox regression analyses, and validated it using GEO datasets. Single-cell sequencing analyses dissected transcriptional heterogeneity and intercellular communication networks, while spatially resolved transcriptomics unveiled spatiotemporal expression patterns and molecular regulatory mechanisms of core genes. With further experimental validation via PCR analysis of patient-derived tissue samples confirming key gene expression patterns. Results: This study identified 23 centrosome amplification-related prognostic genes in pancreatic adenocarcinoma, establishing IFI27, KIF20A, KLK10, SPINK7, and TOP2A as highly specific diagnostic and prognostic biomarkers. The constructed signature was established as an independent prognostic indicator correlating with aggressive clinicopathological characteristics and chemoresistance. Mechanistically linked to enhanced DNA repair capacity and accelerated cell cycle progression, also synergizes with KRAS mutational profiles. Tumor microenvironment analysis revealed significant associations with immunosuppressive. Single-cell resolution demonstrated cellular specificity of IFI27/KLK10 in ductal epithelial cells and fibroblasts, with intercellular communication networks exhibiting multidimensional regulatory features. Spatially resolved transcriptomics delineated tumor-region-specific expression patterns of core genes. While PCR validation on matched tumor/normal tissues confirmed significant differential expression of IFI27, KIF20A, KLK10, and TOP2A. Conclusions: This study deciphers the multidimensional clinic–molecular network orchestrated by centrosome amplification in PDAC, revealing its dual-pathogenic mechanism in fueling tumor aggressiveness through coordinated induction of genomic instability and immunosuppressive microenvironment reprogramming. These findings establish a translational framework for developing centrosome dynamics-based prognostic stratification and molecularly targeted therapeutic strategies. Full article

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ~40% of cases. The efficacy of recently approved, mutant-specific KRAS inhibitors is limited by mutational status as well as intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted ex vivo slice tissue (BEST) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines. Methods: Potency and selectivity of ADT-007 were benchmarked against bortezomib (proteasome inhibitor) and YM155 (survivin inhibitor) using high-content imaging and ATP-based luminescence assays. Apoptosis induction was assessed with Annexin V/propidium iodide and flow cytometry. Results: ADT-007 exhibited high potency and selectivity in KRAS-mutant BEST, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity with minimal cytotoxicity in WT RAS BEST. Annexin V staining confirmed selective induction of apoptosis in KRAS-mutant cells. Conclusions: The selective potency and specificity of ADT-007 warrant further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BEST models for preclinical drug response assessment. Further validation in patient-derived BEST is necessary to evaluate the potential of ADT-007 in clinical settings. Full article

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated genes in human cancer, including non-small cell lung carcinoma (NSCLC). Sustained expression of KRAS is required for survival in KRAS-dependent tumors. KRAS tumors can become independent upon bypassing this addiction. Tissue inhibitor of metalloproteinase-1 (TIMP-1) exhibits a range of novel functions in addition to its initially recognized activity as a physiological inhibitor of matrix metalloproteinases (MMPs). It has repeatedly been associated with cancer progression and poor prognosis in multiple cancers. This study investigates the relationship between TIMP-1 modulation and KRAS dependency in NSCLC. We found an inverse expression of KRAS and TIMP-1 in NSCLC lines. Modulating TIMP-1 levels altered KRAS expression and affected KRAS-dependency features. Overexpression of TIMP-1 decreases the KRAS levels in dependent cells and knocking-down TIMP-1 increases KRAS levels in independent cells with concomitant change in RAS-GTP levels. TIMP-1 modulation influenced apoptosis upon KRAS ablation, with TIMP-1 overexpression decreasing apoptosis in dependent cells and TIMP-1 knockdown increasing it in independent cells. Bioinformatic analysis depicted variant-specific perturbations between KRAS and TIMP-1 expression. Furthermore, EMT marker expression was altered upon TIMP-1 modulation, suggesting the role of TIMP-1 in EMT induction in KRAS-independent cells. These findings emphasize the intricate relationship between TIMP-1 and KRAS in NSCLC, shedding light on potential mechanisms underlying tumor behavior and response to therapy. Full article