Search

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11–12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature. [ABSTRACT FROM AUTHOR]

Introduction: Standard treatment for patients with locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT) with fluoropyrimidines, followed by surgical excision. The newly introduced therapeutic strategies propose intensified regimens or more conservative approaches based on risk stratification algorithms that currently include clinicoradiological criteria but not molecular variables. How to better stratify patients is a burning clinical question, and pharmacogenomics may prove useful in identifying new genetic markers that could be incorporated into clinical algorithms to personalize nCRT. An emerging area could be the evaluation of somatic mutations as potential genetic markers that correlate with patient prognosis. Tumor mutations in the RAS/BRAF genes, as well as microsatellite instability (MSI) status, are currently used in treatment selection for colorectal cancer (CRC); however, their clinical value in LARC is still unclear. Area covered: This literature review discusses the relevant findings on the prognostic role of mutations in the key oncogenes RAS, KRAS, BRAF, PIK3CA, SMAD4 and TP53, including MSI status in LARC patients treated with nCRT. Expert opinion: KRAS proved to be the most promising marker, consistently associated with poorer disease-free survival and overall survival. Therefore, KRAS could be a good candidate for integration into the risk stratification algorithm to develop a personalized treatment. [ABSTRACT FROM AUTHOR]

Background: Oncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge. Methods: In this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082. Results: We demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition. Conclusion: Our study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers. [ABSTRACT FROM AUTHOR]

Despite the considerable progress made in cancer treatment through the development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to this category of drugs. As a result, chemotherapy combination regimens remain the primary treatment approach for this aggressive cancer. In this review, we provide an in-depth analysis of past and ongoing trials on both well-known and novel targets that are being explored in PDAC, including PARP, EGFR, HER2, KRAS, and its downstream and upstream pathways (such as RAF/MEK/ERK and PI3K/AKT/mTOR), JAK/STAT pathway, angiogenesis, metabolisms, epigenetic targets, claudin, and novel targets (such as P53 and plectin). We also provide a comprehensive overview of the significant trials for each target, allowing a thorough glimpse into the past and future of target therapy. The path toward implementing a target therapy capable of improving the overall survival of PDAC is still long, and it is unlikely that a monotherapy target drug will fulfill a meaningful role in addressing the complexity of this cancer. Thus, we discuss the future direction of target therapies in PDAC, trying to identify the more promising target and combination treatments, with a special focus on the more eagerly awaited ongoing trials. [ABSTRACT FROM AUTHOR]

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma continues to be one of the deadliest cancers worldwide. Preclinical studies involving animals rarely include sex as a major biological variable in testing the efficacy of new drugs. In an animal model of pancreatic cancer, we analyzed the impact of sex on the pathological features of the disease and on an experimental small molecule-based therapy tested in vivo for the first time. While the therapy shows potential, the obtained results are confounded by sex-specific effects. This study, therefore, highlights the importance of sex-inclusive research while simultaneously providing a basis for further studies of the therapy tested. Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. [ABSTRACT FROM AUTHOR]

Introduction: Cancer represents a significant global public health concern. In recent years, the incidence of cancer has been on the rise worldwide due to various factors, including diet, environment, and an aging population. Simultaneously, advancements in tumor molecular biology and genomics have led to a shift from systemic chemotherapy focused on disease sites and morphopathology towards precise targeted therapy for driver gene mutations. Therefore, we propose a comprehensive review aimed at exploring the research hotspots and directions in the field of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers over the past decade, providing valuable insights for cancer treatment strategies. Specifically, we aim to present an intellectual landscape using data obtained from the Web of Science (WoS) regarding KRAS mutation. Methods: Bibliometrix, VOSviewer, CiteSpace, and HistCite were employed to conduct scientometric analyses on national publications, influential authors, highly cited articles, frequent keywords, etc. Results: A total of 16,609 publications met the screening criteria and exhibited a consistent annual growth trend overall. Among 102 countries/regions, the United States occupied the vast majority share of the published volume. The journal Oncotarget had the highest circulation among all scientific publications. Moreover, the most seminal articles in this field primarily focus on biology and targeted therapies, with overcoming drug resistance being identified as a future research direction. Conclusion: The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast. [ABSTRACT FROM AUTHOR]

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab. [ABSTRACT FROM AUTHOR]

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRASG12C and pan-RAS inhibitors in KRAS-mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers. [ABSTRACT FROM AUTHOR]

Poorly differentiated colonic carcinoma with rhabdoid features is a rarely described entity. Our knowledge regarding the molecular phenotype of the tumor is evolving. We herein report a similar tumor with rhabdoid differentiation identified in the splenic flexure, which on histological examination showed a poorly differentiated phenotype with epithelioid to spindled morphology, tumor giant cells, and rhabdoid differentiation. The tumor was mismatch repair-proficient, deficient of INI1/SMARCB1, KRAS mutated (A146×), BRAFV600E mutated (c.1799T > A), and NRAS wild-type, indicating serrated differentiation in the tumor. The patient died after 3.5 months post-surgery. INI1-deficient poorly differentiated carcinoma of the colon is a rare, aggressive colonic malignancy showing a serrated phenotype. Routine identification and subtyping are important keeping in mind the distinct tumor phenotype, resistance to conventional chemotherapy, and dismal prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of proprietary drugs targeting KRAS-mutant tumors has historically been a formidable challenge. This difficulty stems from the high affinity of RAS proteins for GTP and the lack of a hydrophobic "pocket" conducive to drug binding. However, the emergence of CRISPR technology, a groundbreaking gene-editing tool, has revolutionized tumor studies, particularly those focusing on KRAS mutations. This article offers a review of both fundamental and translational research leveraging the CRISPR system in the context of KRAS-mutant cancer. It encapsulates recent strides made in understanding KRAS biology's mechanistic nuances, shedding light on pivotal themes such as drug resistance, anti-tumor immune responses, epigenetic regulation, and the exploitation of synthetic lethality by mutant KRAS. In conclusion, the article touches upon the current limitations of employing CRISPR technology in KRAS-related research, while also suggesting avenues for future refinement and optimization in this dynamic field. Once considered "undruggable" due to the strong affinity of RAS proteins for GTP and the structural lack of a hydrophobic "pocket" for drug binding, the development of proprietary therapies for KRAS-mutant tumors has long been a challenging area of research. CRISPR technology, the most successful gene-editing tool to date, is increasingly being utilized in cancer research. Here, we provide a comprehensive review of the application of the CRISPR system in basic and translational research in KRAS-mutant cancer, summarizing recent advances in the mechanistic understanding of KRAS biology and the underlying principles of drug resistance, anti-tumor immunity, epigenetic regulatory networks, and synthetic lethality co-opted by mutant KRAS. [ABSTRACT FROM AUTHOR]

In recent literature reviews, we concluded that the possibility that endometrial molecular aberrations are the sole or a necessary determinant of endometriosis and the Tissue Injury and Repair (TIAR) theory are yet to be convincingly proven. Here, we critically examine the theory that adenomyosis and endometriosis represent different phenotypes of a single disease. A common etiopathology for adenomyosis and endometriosis has been suggested because both conditions entail the presence of endometrial tissue at locations other than the lining of the uterus. There are wide differences in reported disease incidence and prevalence and, consequently, in estimates of the coexistence of both conditions. There are some similarities but also differences in their clinical features and predisposing factors. Each condition has a range of subtypes. These differences alone pose the question of whether subtypes of endometriosis and adenomyosis have different etiopathologies, and, in turn, this raises the question of whether they all share a common etiology. It is debatable whether the recognized differences between the eutopic endometrium in adenomyosis and endometriosis compared to those in unaffected women are the cause or the effect of the disease. The finding of common mutations, particularly of KRAS, lend support to the notion of shared predisposing factors, but this alone is insufficient evidence of causation. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Civil Engineering (Polish Academy of Sciences) is the property of Polish Academy of Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) is cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) is an emerging standard of care in the metastatic setting. An evolving understanding of PDAC pathogenesis is driving a shift toward targeted therapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval for maintenance therapy in BRCA-mutated mPDAC along with other targeted agents receiving disease-agnostic approvals including for PDAC with rare fusions and mismatch repair deficiency. Ongoing research continues to identify and evaluate an expanding array of targeted therapies for PDAC. This review provides a brief overview of standard therapies for PDAC and an emphasis on current and emerging targeted therapies. There is notable potential for targeted therapies for KRAS-mutated PDAC with opportunity for meaningful benefit for a sizable portion of patients with this disease. Further, emerging approaches are focused on novel immune, tumor microenvironment, and synthetic lethality strategies. [ABSTRACT FROM AUTHOR]

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11–12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.