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Cancers Apr 2024Tipifarnib is the only targeted therapy breakthrough for -mutant (mt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of mt...
Tipifarnib is the only targeted therapy breakthrough for -mutant (mt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of mt cancers are difficult to explore given the low frequency of mt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 mt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. mt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). mt was absent in Her2+ BC regardless of hormone receptor status. mt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in wt, = 0.002). The tumor microenvironment (TME) of mt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all < 0.05). Finally, mt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of mt tumors that may help to identify new targets and guide future clinical trial design.
PubMed: 38672653
DOI: 10.3390/cancers16081572 -
Medicine Mar 2024The Golgi apparatus plays a crucial role in intracellular protein transportation, processing, and sorting. Dysfunctions of the Golgi apparatus have been implicated in...
The Golgi apparatus plays a crucial role in intracellular protein transportation, processing, and sorting. Dysfunctions of the Golgi apparatus have been implicated in tumorigenesis and drug resistance. This study aimed to investigate the prognostic and treatment response assessment value of Golgi apparatus-related gene (GARGs) features in gastric cancer patients. Transcriptome data and clinical information of gastric cancer patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Cox regression analysis was employed to assess the prognostic significance of GARGs and construct risk features. The immune landscape, drug sensitivity, immune therapy response, gene expression patterns, and somatic mutation characteristics were analyzed between different risk groups. A nomogram model for predicting gastric cancer prognosis was developed and evaluated. Among 1643 GARGs examined, 365 showed significant associations with gastric cancer prognosis. Five independent prognostic GARGs (NGF, ABCG1, CHAC1, GBA2, PCSK7) were selected to construct risk features for gastric cancer patients. These risk features effectively stratified patients into high-risk and low-risk groups, with the former exhibiting worse prognosis than the latter. Patients in the high-risk group displayed higher levels of immune cell infiltration, while the expression levels of NGF, CHAC1, GBA2, PCSK7 were significantly correlated with immune cell infiltration. Notably, the low-risk group exhibited higher sensitivity to epothilone.B, metformin, and tipifarnib compared to the high-risk group. Moreover, patients in the low-risk group demonstrated greater responsiveness to immune therapy than those in the high-risk group. In terms of biological processes and KEGG pathways related to immunity regulation, significant suppression was observed in the high-risk group compared to the low-risk group; meanwhile cell cycle pathways exhibited significant activation in the high-risk group. Furthermore, the low-risk group exhibited a higher tumor mutation burden compared to the high-risk group. The risk features derived from GARGs, in conjunction with age, were identified as independent risk factors for gastric cancer. The nomogram incorporating these factors demonstrated improved performance in predicting gastric cancer prognosis. Our study established risk features derived from GARGs that hold potential clinical utility in prognostic assessment and immune therapy response evaluation of gastric cancer patients.
Topics: Humans; Stomach Neoplasms; Prognosis; Immunotherapy; Golgi Apparatus; Subtilisins
PubMed: 38489711
DOI: 10.1097/MD.0000000000037439 -
Magyar Onkologia Sep 2023In silico studies raised the possibility that farnesyltransferase inhibitors (FTIs) may have antitumoral effects on KRAS mutant cancer cells. Accordingly, we have tested...
In silico studies raised the possibility that farnesyltransferase inhibitors (FTIs) may have antitumoral effects on KRAS mutant cancer cells. Accordingly, we have tested FTIs (tipifarnib and lonafarnib) in G12C mutant human cancer cell lines in vitro and in vivo. We have discovered that the combination of the two drugs has a synergistic antitumoral effect. Next, we have tested FTIs on G12D mutant human cancer cell lines and found that the combination has antitumoral effect in various preclinical cancer models. At last, we have also tested FTIs on G12V mutant human cancer cells and again we have detected antitumoral effects. We suggest that FTIs may have clinical relevance outside the HRAS mutant cancers.
Topics: Humans; Farnesyltranstransferase; Proto-Oncogene Proteins p21(ras); Enzyme Inhibitors; Neoplasms
PubMed: 38484318
DOI: No ID Found -
British Journal of Cancer Apr 2024Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer....
BACKGROUND
Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors.
METHODS
Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown.
RESULTS
Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models.
DISCUSSION
Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
Topics: Humans; Animals; Adenocarcinoma; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Adenocarcinoma of Lung; Lung Neoplasms; Disease Models, Animal; Enzyme Inhibitors; Transferases; Colorectal Neoplasms; Mutation
PubMed: 38278976
DOI: 10.1038/s41416-024-02586-x -
IScience Jan 2024Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an resistance assay (ISRA) that reliably...
Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in -mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs. We additionally modeled resistance to targeted therapies including the KRAS inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.
PubMed: 38226159
DOI: 10.1016/j.isci.2023.108711 -
Clinical Case Reports Oct 2023mutations are frequent genetic alterations in epithelial-myoepithelial carcinoma, and they may be useful as ancillary molecular tests and predictive molecular tests for...
mutations are frequent genetic alterations in epithelial-myoepithelial carcinoma, and they may be useful as ancillary molecular tests and predictive molecular tests for targeted therapy with tipifarnib.
PubMed: 37881200
DOI: 10.1002/ccr3.8099 -
Frontiers in Molecular Biosciences 2023Hepatocellular carcinoma (HCC) is extremely malignant and difficult to treat. The adenoviral early region 2 binding factors (E2Fs) target pathway is thought to have a...
Hepatocellular carcinoma (HCC) is extremely malignant and difficult to treat. The adenoviral early region 2 binding factors (E2Fs) target pathway is thought to have a major role in tumor growth. This study aimed to identify a predictive E2F target signature and facilitate individualized treatment for HCC patients. We constructed an E2F target-related gene profile using univariate COX and LASSO regression models and proved its predictive efficacy in external cohorts. Furthermore, we characterized the role of the E2F target pathway in pathway enrichment, immune cell infiltration, and drug sensitivity of HCC. Lasso Cox regression created an E2F target-related gene signature of GHR, TRIP13, and CDCA8. HCC patients with high risk were correlated with shorter survival time, immune evasion, tumor stem cell characteristics and high sensitivity to Tipifarnib and Camptothecin drugs. Hepatocellular carcinoma prognosis was predicted by an E2F target signature. This finding establishes the theoretical usefulness of the E2F target route in customized identification and treatment for future research.
PubMed: 37854038
DOI: 10.3389/fmolb.2023.1266515 -
International Journal of General... 2023associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of...
BACKGROUND
associated protein 1 () is shown to regulate cell proliferation and cancer progression. However, the immune-infiltrating correlation and the therapeutics guidance of in hepatocellular carcinoma (HCC) still need further investigation.
METHODS
In this study, comprehensive bioinformatic analysis of on differential expression, clinicopathologic correlation, prognostic value, and function enrichment were performed in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO; GSE14520 and GSE76427), and International Cancer Genome Consortium (ICGC) datasets. Besides, the Guangxi cohort containing 50 pairs HCC and adjacent non-cancerous samples from First Affiliated Hospital of Guangxi Medical University was served as validation cohort. Moreover, we explored the predictive value of to therapeutics response and its underlying correlation with HCC immunoinfiltration.
RESULTS
was significantly overexpressed in HCC tissues and had a high diagnostic value of HCC. The shorter survival time and poorer clinical features were showed when upregulated, and then a nomogram featuring expression and other clinicopathologic factors was established to predict prognosis. In CIBERSORT analysis, higher T cells follicular helper but lower T cells CD4+ memory resting infiltration levels were exhibited when upregulated. The ssGSEA analysis demonstrated that high- expression subgroup had higher macrophages, Th2 and Treg cells infiltration levels, but lower type II IFN response function. Furthermore, high- expression subgroup exhibited the upregulated expression levels of immune-related checkpoint genes, but lower IPS and TIDE scores which suggested a possibly better immunotherapy response. The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib.
CONCLUSION
Taken together, is a potential diagnostic and prognostic biomarker. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.
PubMed: 37789880
DOI: 10.2147/IJGM.S431206 -
Cancer Research Oct 2023Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for...
Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. Using an impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Precision Medicine; Cell Line, Tumor; Head and Neck Neoplasms; TOR Serine-Threonine Kinases; Class I Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras)
PubMed: 37779427
DOI: 10.1158/0008-5472.CAN-23-1858 -
Reports of Biochemistry & Molecular... Apr 2023Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT...
BACKGROUND
Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation.
METHODS
The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.
RESULTS
We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.
CONCLUSIONS
Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.
PubMed: 37724142
DOI: 10.52547/rbmb.12.1.74