Prevalence of the Mutational Status of V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) in Metastatic Colorectal Cancer (mCRC) in Argentine Patients
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ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2086001 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRASG12C inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRASG12C inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.
| S-EPMC9065471 | biostudies-literature
Project description:The combination of capecitabine and cetuximab as first-line therapy will result in improved progression free survival compared to single agent capecitabine in patients with KRAS wild type colorectal cancer. Patients who are not able or willing to take Oxaliplatin/Irinotecan combination therapy are eligible for this study.
| 2076338 | ecrin-mdr-crc
Project description:IntroductionSpecific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) despite treatment advances in other mutation-driven subgroups.Patients and methodsIn this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib in combination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients' first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points.ResultsTwenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3 [14.3%]). No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%-75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2-5.6 months) and 7.4 months (90% CI, 4.0-15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition.ConclusionThe additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.
| S-EPMC6420784 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell-cell and cell-extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future.
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Project description:Bevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.We established xenograft mice models harboring Kirsten rat sarcoma oncogene homolog (KRAS) mutations based on the A549 cell line, and tested the responses of xenograft tumors to a series of drugs in ex vivo and in vivo experiments. Changes in transcriptive level were analyzed by ribonucleic acid (RNA) sequencing and the expressions of connexins were determined by immunohistochemistry staining.A549 cell mutation type (KRAS G12S) was confirmed by sequencing. After treating the xenograft tumors with BV, the median interval time from BV administration to tumor volume more than 2.5-fold of the original was 37 days, compared with 21 days in the control (P = 0.025). A549 cells showed resistantance to selumitinib (MEK inhibitor) but were sensitive to selumitinib plus BEZ235 (phosphoinositide 3-kinase/mammalian target of rapamycin dual inhibitor). However, selumitinib could effectively reverse the resistance to BV in in vivo experiments. RNA sequencing showed that mouse genes, but not human genes, activated the mitogen-activated protein kinase signaling pathway, accompanied by activation of the Wnt and Hedgehog pathways. Connexin43 (S261) was phosphorylated before and during BV treatment, and subsequently transitioned to negative phosphorylated-connexin 43-S261 after resistance to BV.Combining an MEK inhibitor with BV was a potential strategy to reverse initial BV resistance. Phosphorylated-connexin 43 might be associated with the response to BV.
| S-EPMC4846615 | biostudies-other
Project description:Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.
| S-EPMC10930734 | biostudies-literature
Project description:This study is a global, multicenter, open-label phase 1b and randomized, double-blinded, 2 part, phase 2 study designed to evaluate the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus panitumumab alone in patients with metastatic colorectal cancer whose tumors are wild-type KRAS status.
| 2063797 | ecrin-mdr-crc
Project description:Background: Non-small cell lung cancer with brain metastasis (NSCLCBM) is normally observed in advanced-stage patients. Bevacizumab has shown to improve survival in the first-line treatment of metastatic brain NSCLC when added as a bolus plus irinotecan. However, a better understanding of the molecular mechanism is required to further drive progress in this field. Methods: A total of 155 patients were selected, including 42.10% with Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant tumors. Of the 155 patients, 62.04% had developed brain metastasis (BM). Seven functional single-nucleotide polymorphisms (SNPs) in the Kras gene were extracted from the HapMap SNP database and were used for genotyping. The haplologit command in Statistical Software for Data Science (STATA) was used to model the association between haplotypes and case status. A Cox analysis was used to evaluate the prognostic value of the SNPs. Results: Among the patients treated with combination regimens, recurrence after local treatment was more frequent in those with two types of Kras mutations (odds ratio [OR] = 2.033 [0.5015-4.2552], p = 0.009). Among the patients with untreated BM, overall survival was shorter than that of patients with Kras mutations according to univariate analysis (OR = 5.130 [1.240-41.012], p = 0.033). Conclusions: Kras mutations have a predictive role for BM recurrence and outcome in patients with NSCLC treated with bevacizumab combination regimens.
| S-EPMC9150132 | biostudies-literature
Project description:ObjectiveTo develop and validate radiomics models based on multiphasic CT in predicting Kirsten rat sarcoma virus (KRAS) gene mutation status in patients with colorectal cancer (CRC).Materials and methodsA total of 231 patients with pathologically confirmed CRC were retrospectively enrolled and randomly divided into training(n=184) and test groups(n=47) in a ratio of 4:1. A total of 1316 quantitative radiomics features were extracted from non-contrast phase (NCP), arterial-phase (AP) and venous-phase (VP) CT for each patient. Four steps were applied for feature selection including Spearman correlation analysis, variance threshold, least absolute contraction and selection operator, and multivariate stepwise regression analysis. Clinical and pathological characteristics were also assessed. Subsequently, three classification methods, logistic regression (LR), support vector machine (SVM) and random tree (RT) algorithm, were applied to develop seven groups of prediction models (NCP, AP, VP, AP+VP, AP+VP+NCP, AP&VP, AP&VP&NCP) for KRAS mutation prediction. The performance of these models was evaluated by receiver operating characteristics curve (ROC) analysis.ResultsAmong the three groups of single-phase models, the AP model, developed by LR algorithm, showed the best prediction performance with an AUC value of 0.811 (95% CI:0.685-0.938) in the test cohort. Compared with the single-phase models, the dual-phase (AP+VP) model with the LR algorithm showed better prediction performance (AUC=0.826, 95% CI:0.700-0.952). The performance of multiphasic (AP+VP+NCP) model with the LR algorithm (AUC=0.811, 95%CI: 0.679-0.944) is comparable to the model with the SVM algorithm (AUC=0.811, 95%CI: 0.695-0.918) in the test cohort, but the sensitivity, specificity, and accuracy of the multiphasic (AP+VP+NCP) model with the LR algorithm were 0.810, 0.808, 0.809 respectively, which were highest among these seven groups of prediction models in the test cohort.ConclusionThe CT radiomics models have the potential to predict KRAS mutation in patients with CRC; different phases may affect the predictive efficacy of radiomics model, of which arterial-phase CT is more informative. The combination of multiphasic CT images can further improve the performance of radiomics model.
| S-EPMC9263192 | biostudies-literature
Project description:This study is open to adults with advanced bowel cancer (colorectal cancer) with a KRAS mutation. This is a study in people for whom previous treatment was not successful and surgery is not a treatment option.
The purpose of this study is to find the highest dose of BI 1701963 that people with bowel cancer can tolerate when taken together with a medicine called irinotecan. The study also tests whether BI 1701963 in combination with irinotecan is able to make tumours shrink. BI 1701963 may help to turn off KRAS. Activating KRAS mutations make tumours grow. Irinotecan is a medicine to treat bowel cancer.
Participants can stay in the study as long as they benefit from treatment and can tolerate it.
During this time, participants take BI 1701963 as tablet once a day and get irinotecan as infusion every two weeks. The doctors regularly monitor the size of the tumour. The doctors also collect information on any health problems of the participants.
| 2357573 | ecrin-mdr-crc