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Keywords = KRAS G12D

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12 pages, 294 KiB  
Review
Targeting Advanced Pancreatic Ductal Adenocarcinoma: A Practical Overview
by Chiara Citterio, Stefano Vecchia, Patrizia Mordenti, Elisa Anselmi, Margherita Ratti, Massimo Guasconi and Elena Orlandi
Gastroenterol. Insights 2025, 16(3), 26; https://doi.org/10.3390/gastroent16030026 - 30 Jul 2025
Viewed by 251
Abstract
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with a five-year overall survival rate below 10%. While the introduction of multi-agent chemotherapy regimens has improved outcomes marginally, most patients with advanced disease continue to have limited therapeutic options. Molecular [...] Read more.
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with a five-year overall survival rate below 10%. While the introduction of multi-agent chemotherapy regimens has improved outcomes marginally, most patients with advanced disease continue to have limited therapeutic options. Molecular profiling has uncovered actionable genomic alterations in select subgroups of PDAC, yet the clinical impact of targeted therapies remains modest. This review aims to provide a clinically oriented synthesis of emerging molecular targets in PDAC, their therapeutic relevance, and practical considerations for biomarker testing, including current FDA and EMA indications. Methods: A narrative review was conducted using data from PubMed, Embase, Scopus, and international guidelines (NCCN, ESMO, ASCO). The selection focused on evidence published between 2020 and 2025, highlighting molecularly defined PDAC subsets and the current status of targeted therapies. Results: Actionable genomic alterations in PDAC include KRAS G12C mutations, BRCA1/2 and PALB2-associated homologous recombination deficiency, MSI-H/dMMR status, and rare gene fusions involving NTRK, RET, and NRG1. While only a minority of patients are eligible for targeted treatments, early-phase trials and real-world data have shown promising results in these subgroups. Testing molecular profiling is increasingly standard in advanced PDAC. Conclusions: Despite the rarity of targetable mutations, systematic molecular profiling is critical in advanced PDAC to guide off-label therapy or clinical trial enrollment. A practical framework for identifying and acting on molecular targets is essential to bridge the gap between precision oncology and clinical management. Full article
(This article belongs to the Special Issue Advances in the Management of Gastrointestinal and Liver Diseases)
10 pages, 738 KiB  
Article
In Vitro Evaluation of Electrochemotherapy Combined with Sotorasib in Pancreatic Carcinoma Cell Lines Harboring Distinct KRAS Mutations
by Tanja Jesenko, Masa Omerzel, Tina Zivic, Gregor Sersa and Maja Cemazar
Int. J. Mol. Sci. 2025, 26(15), 7165; https://doi.org/10.3390/ijms26157165 - 24 Jul 2025
Viewed by 291
Abstract
Pancreatic cancer is among the deadliest malignancies, with limited treatment options and poor prognosis. Novel strategies are therefore urgently needed. Sotorasib, a KRAS G12C-specific inhibitor, offers targeted treatment for a small subset of patients with this mutation. Electrochemotherapy (ECT), which enhances the cytotoxicity [...] Read more.
Pancreatic cancer is among the deadliest malignancies, with limited treatment options and poor prognosis. Novel strategies are therefore urgently needed. Sotorasib, a KRAS G12C-specific inhibitor, offers targeted treatment for a small subset of patients with this mutation. Electrochemotherapy (ECT), which enhances the cytotoxicity of chemotherapeutic agents through electroporation-induced membrane permeabilization, has shown promise in various tumor types, including deep-seated malignancies such as pancreatic cancer. Combining ECT with sotorasib may potentiate antitumor effects in KRAS G12C-mutated pancreatic cancer; however, preclinical data on such combinations are lacking. This proof-of-concept study evaluated the cytotoxic effects of ECT using bleomycin (BLM) or cisplatin (CDDP) in combination with sotorasib in KRAS G12C-mutated MIA PaCa-2 and KRAS G12D-mutated PANC-1 pancreatic cancer cell lines. ECT alone significantly reduced cell viability, particularly in MIA PaCa-2 cells, where electric pulses induced approximately 75% cell death. Combining ECT with sotorasib resulted in an additive effect on KRAS G12C-mutated MIA PaCa-2 cells, though no synergy was observed, likely due to the high intrinsic sensitivity to electric pulses. These results support the potential of combining physical and molecular therapies in a subset of pancreatic cancer patients and lay the groundwork for further in vivo studies to optimize treatment parameters and explore clinical translatability. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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34 pages, 2332 KiB  
Review
Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients?
by Kamila Krupa, Marta Fudalej, Emilia Włoszek, Hanna Miski, Anna M. Badowska-Kozakiewicz, Dominika Mękal, Michał P. Budzik, Aleksandra Czerw and Andrzej Deptała
Cancers 2025, 17(15), 2453; https://doi.org/10.3390/cancers17152453 - 24 Jul 2025
Viewed by 821
Abstract
Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation [...] Read more.
Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article
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24 pages, 5400 KiB  
Article
Design, Synthesis, Anticancer Evaluation and Molecular Docking of Pyrimidine, Pyrido[4,3-d]pyrimidine and 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine Derivatives as Novel KRAS-G12D Inhibitors and PROTACs
by Hailong Yang, Lu Gan and Huabei Zhang
Pharmaceuticals 2025, 18(5), 696; https://doi.org/10.3390/ph18050696 - 8 May 2025
Viewed by 1631
Abstract
Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate [...] Read more.
Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC50 = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC50 > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC50 = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC50 = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development. Full article
(This article belongs to the Section Medicinal Chemistry)
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10 pages, 4900 KiB  
Case Report
Prolonged Survival Outcome in a Patient with Refractory Metastatic Colorectal Cancer Treated with Regorafenib Plus 5-Fluorouracil: A Case Report and Literature Review
by Abdullah Esmail, Bayan Khasawneh, Ebtesam Al-Najjar, Raed Zaidan and Maen Abdelrahim
Reports 2025, 8(2), 59; https://doi.org/10.3390/reports8020059 - 30 Apr 2025
Viewed by 802
Abstract
Background: The use of regorafenib and 5-fluorouracil in the management of refractory metastatic colorectal cancer has gained increasing attention due to their demonstrated efficacy in extending the survival of patients with colorectal cancer. This study aims to discuss the effect of using regorafenib [...] Read more.
Background: The use of regorafenib and 5-fluorouracil in the management of refractory metastatic colorectal cancer has gained increasing attention due to their demonstrated efficacy in extending the survival of patients with colorectal cancer. This study aims to discuss the effect of using regorafenib and 5-fluorouracil combination therapy in refractory metastatic colorectal cancer patients. Case Presentation: We present a case report of a 68-year-old female patient with KRAS G12D and PIK3CA mutations who was diagnosed with stage IV-C colon cancer. She was referred to hospice care and subsequently received therapeutic intervention with 56 cycles of regorafenib and 5-fluorouracil for 31 months while maintaining stable disease (SD). The patient exhibited good tolerance with minimal adverse effects, including Grade I-II Hand–Foot Syndrome. Conclusions: Our case showed the feasibility of using Regorafenib and 5-fluorouracil combination therapy in stage IV refractory metastatic colorectal cancer treatment, which resulted in an improvement in the overall survival after she was referred to Hospice care. Utilizing this case report may provide valuable input in managing refractory metastatic colorectal cancer, given the prolonged survival and the clinical meaningfulness of this regimen in our patient. Full article
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18 pages, 6470 KiB  
Article
Mapping the Interactome of KRAS and Its G12C/D/V Mutants by Integrating TurboID Proximity Labeling with Quantitative Proteomics
by Jiangwei Song, Busong Wang, Mingjie Zou, Haiyuan Zhou, Yibing Ding, Wei Ren, Lei Fang and Jingzi Zhang
Biology 2025, 14(5), 477; https://doi.org/10.3390/biology14050477 - 26 Apr 2025
Viewed by 1150
Abstract
KRAS mutations are major drivers of human cancers, yet how distinct mutations rewire protein interactions and metabolic pathways to promote tumorigenesis remains poorly understood. To address this, we systematically mapped the protein interaction networks of wild-type KRAS and three high-frequency oncogenic mutants (G12C, [...] Read more.
KRAS mutations are major drivers of human cancers, yet how distinct mutations rewire protein interactions and metabolic pathways to promote tumorigenesis remains poorly understood. To address this, we systematically mapped the protein interaction networks of wild-type KRAS and three high-frequency oncogenic mutants (G12C, G12D, and G12V) using TurboID proximity labeling coupled with quantitative proteomics. Bioinformatic analysis revealed mutant-specific binding partners and metabolic pathway alterations, including significant enrichment in insulin signaling, reactive oxygen species regulation, and glucose/lipid metabolism. These changes collectively drive tumor proliferation and immune evasion. Comparative analysis identified shared interactome shifts across all mutants: reduced binding to LZTR1, an adaptor for KRAS degradation, and enhanced recruitment of LAMTOR1, a regulator of mTORC1-mediated growth signaling. Our multi-dimensional profiling establishes the first comprehensive map of KRAS-mutant interactomes and links specific mutations to metabolic reprogramming. These findings provide mechanistic insights into KRAS-driven malignancy and highlight LZTR1 and LAMTOR1 as potential therapeutic targets. The study further lays a foundation for developing mutation-specific strategies to counteract KRAS oncogenic signaling. Full article
(This article belongs to the Special Issue Proteomics and Human Diseases)
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13 pages, 303 KiB  
Article
Regional and Gender-Based Distribution of KRAS Mutations in Metastatic Colorectal Cancer Patients in Turkey: An Observational Study
by Nurullah Ilhan, Faysal Dane, Erdem Goker, Kazım Uygun, Bülent Orhan, Kerem Okutur, İlkay Tuğba Ünek, Abdurrahman Işıkdoğan, Ahmet Bilici, Nurullah Zengin, Necati Alkış, İdris Yücel, Hatice Odabaş, Berna Ömür Öksüzoğlu, Akif Doğan, Hande Nur Erölmez and Mahmut Gümüş
Medicina 2025, 61(4), 694; https://doi.org/10.3390/medicina61040694 - 10 Apr 2025
Viewed by 779
Abstract
Background and Objectives: KRAS genes are among the most prominent oncogenes that trigger tumor formation in colorectal cancer (CRC) and serve as predictive biomarkers for resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) patients. However, the prevalence and mutation spectrum of the [...] Read more.
Background and Objectives: KRAS genes are among the most prominent oncogenes that trigger tumor formation in colorectal cancer (CRC) and serve as predictive biomarkers for resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) patients. However, the prevalence and mutation spectrum of the KRAS gene family in mCRC patients in Turkey have not been sufficiently analyzed. This study investigates the frequency and distribution of mutations in the KRAS gene family across different regions of Turkey and examines gender-related variations. Materials and Methods: This multicenter observational study included 2458 histologically confirmed mCRC patients collected from 52 centers across Turkey. In a central laboratory, KRAS mutations in codons 12 and 13 were analyzed using polymerase chain reaction (PCR). Statistical analyses were performed using chi-square tests and Monte Carlo simulations, with a significance threshold set at p < 0.05. Results: Depending on the region, KRAS mutations were detected in 45% of patients, ranging from 39.6% to 47.5%. The mutation rate was significantly higher in female patients (48.8%) compared to male patients (42.6%) (p = 0.002). Codon 12 mutations were more frequent than codon 13 mutations. G12D, G12V, and G13D mutations accounted for 80% of all detected mutations. The G12V mutation was prevalent in female patients (p = 0.007). Based on region, mutation diversity was similar, and no statistically significant difference was found (p > 0.05). Conclusions: This large-scale, multicenter study provides the most comprehensive dataset of KRAS mutations in mCRC patients in Turkey. This study revealed regional trends, as well as gender differences. The findings highlight the importance of routine KRAS genotyping in guiding personalized treatment strategies, especially regarding candidate selection for anti-EGFR therapies. Further research is required to elucidate the prognostic and therapeutic implications of specific KRAS mutations. Full article
(This article belongs to the Section Oncology)
17 pages, 2119 KiB  
Article
Trends in Overall Survival in Lung Adenocarcinoma with EFGR Mutation, KRAS Mutation, or No Mutation
by Martin Faehling, Sabine Fallscheer, Birgit Schwenk, Harald Seifarth, Jörn Sträter, Claudia Lengerke and Petros Christopoulos
Cancers 2025, 17(7), 1237; https://doi.org/10.3390/cancers17071237 - 5 Apr 2025
Viewed by 848
Abstract
Background: Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups. Methods: This real-world analysis (KOMPASS [...] Read more.
Background: Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups. Methods: This real-world analysis (KOMPASS study) included stage IV lung-adenocarcinoma patients with either EGFR, KRAS, or no mutation. Patients were assigned to the “current” EGFR, KRAS, or no-mutation cohort if they had mutation testing using NGS (n = 199; median date of diagnosis 2021). If they had an EGFR PCR test only, they were assigned to the “historic” EGFR or no-mutation cohort (n = 127; median date of diagnosis 2014). Results: Both the current and the historic EGFR cohorts had significantly longer OS than the respective no-mutation cohorts (HR 0.58 and 0.60, respectively). The current no-mutation and EGFR cohorts had a strong trend to longer OS than the respective historic cohorts. In the no-mutation cohorts, the improvement was due to an increase in long-term survivors (HR 0.71), whereas in the EGFR mutation cohorts, the median OS was improved without long-term survivors (HR 0.70). The KRAS cohort showed OS like the no-mutation cohort, with a plateau of long-term survivors around 20%. Conclusions: A comparison of our data with that of the phase III trials KEYNOTE-189 and FLAURA suggests that the improved outcomes are due to the use of CPIs or osimertinib. The clinical trial results are well translated into real-world clinical practice with comparable OS. KRAS patients benefit from CPI treatment like no-mutation patients. Full article
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6 pages, 6684 KiB  
Interesting Images
Lung Adenocarcinoma Exhibiting Thanatosomes (Hyaline Bodies), Cytoplasmic Clearing, and Nuclear Pleomorphism, with a KRAS Mutation
by Mitsuhiro Tachibana, Yutaro Ito, Ryo Fujikawa, Kei Tsukamoto, Masahiro Uehara, Jun Kobayashi and Takuo Hayashi
Diagnostics 2025, 15(7), 894; https://doi.org/10.3390/diagnostics15070894 - 1 Apr 2025
Viewed by 617
Abstract
Since epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were introduced in 2004, various driver gene mutations have been identified in non-small cell lung cancer, particularly adenocarcinoma, where mutations are typically mutually exclusive. EGFR and Kirsten rat sarcoma viral oncogene (KRAS) mutations are [...] Read more.
Since epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were introduced in 2004, various driver gene mutations have been identified in non-small cell lung cancer, particularly adenocarcinoma, where mutations are typically mutually exclusive. EGFR and Kirsten rat sarcoma viral oncogene (KRAS) mutations are most prevalent in Japan, with routine testing now standard. However, hematoxylin and eosin staining often fails to detect mutations, except in cases such as ALK fusion lung cancer. We report a 76-year-old non-smoking Japanese woman diagnosed with adenocarcinoma confirmed as KRAS G12D/S-positive. Histological features, including thanatosomes (hyaline globules), nuclear pleomorphism, and cytoplasmic clearing, may aid in identifying mutations. Numerous thanatosomes were identified, some containing nuclear dust. Thanatosomes revealed periodic acid–Schiff reactivity with diastase resistance, fuchsinophilia with Masson’s trichrome stain, and dark blue-black color with Mallory’s PTAH stain. This is the first report linking thanatosomes in KRAS-mutant pulmonary adenocarcinoma to apoptosis via cleaved caspase-3 staining. Full article
(This article belongs to the Section Pathology and Molecular Diagnostics)
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22 pages, 5075 KiB  
Article
Evaluation of the Inhibitory Potential of Apigenin and Related Flavonoids on Various Proteins Associated with Human Diseases Using AutoDock
by Tanat Peanlikhit, Uma Aryal, James S. Welsh, Kenneth R. Shroyer and Kanokporn Noy Rithidech
Int. J. Mol. Sci. 2025, 26(6), 2548; https://doi.org/10.3390/ijms26062548 - 12 Mar 2025
Viewed by 1255
Abstract
We used molecular docking to determine the binding energy and interactions of apigenin and 16 related flavonoids, with 24 distinct proteins having diverse biological functions. We aimed to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids impacting their [...] Read more.
We used molecular docking to determine the binding energy and interactions of apigenin and 16 related flavonoids, with 24 distinct proteins having diverse biological functions. We aimed to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids impacting their binding energy. Our results demonstrate that apigenin exhibits high binding energies (a surrogate for binding affinity or inhibitory potential) to all tested proteins. The strongest binding energy was −8.21 kcal/mol for p38 mitogen-activated protein kinases, while the weakest was −5.34 kcal/mol for cyclin-dependent kinase 4. Apigenin and many other flavonoids showed high binding energies on xanthine oxidase (1.1–1.5 fold of febuxostat) and DNA methyltransferases (1.1–1.2 fold of azacytidine). We uncovered high binding energies of apigenin and certain flavonoids with mutated Kirsten rat sarcoma viral oncogene homolog at G12D (KRAS G12D), G12V, and G12C. Consequently, apigenin and certain flavonoids have the potential to effectively inhibit pan-KRAS oncogenic activity, not just on specific KRAS mutations. Apigenin and certain flavonoids also have high binding energies with aromatase (involved in estrogen production) and bacterial infections, i.e., DNA gyrase B and 3R-hydroxy acyl-ACP dehydratase (FABZ). Our findings are pivotal in identifying specific flavonoids that can effectively inhibit targeted proteins, paving the way for the development of innovative flavonoid-based drugs. Full article
(This article belongs to the Special Issue Drug Discovery Based on Natural Products)
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26 pages, 2937 KiB  
Article
Inflammatory Stimuli and Fecal Microbiota Transplantation Accelerate Pancreatic Carcinogenesis in Transgenic Mice, Accompanied by Changes in the Microbiota Composition
by Agnieszka Świdnicka-Siergiejko, Jarosław Daniluk, Katarzyna Miniewska, Urszula Daniluk, Katarzyna Guzińska-Ustymowicz, Anna Pryczynicz, Milena Dąbrowska, Małgorzata Rusak, Michał Ciborowski and Andrzej Dąbrowski
Cells 2025, 14(5), 361; https://doi.org/10.3390/cells14050361 - 28 Feb 2025
Cited by 1 | Viewed by 985
Abstract
An association between gut microbiota and the development of pancreatic ductal adenocarcinoma (PDAC) has been previously described. To better understand the bacterial microbiota changes accompanying PDAC promotion and progression stimulated by inflammation and fecal microbiota transplantation (FMT), we investigated stool and pancreatic microbiota [...] Read more.
An association between gut microbiota and the development of pancreatic ductal adenocarcinoma (PDAC) has been previously described. To better understand the bacterial microbiota changes accompanying PDAC promotion and progression stimulated by inflammation and fecal microbiota transplantation (FMT), we investigated stool and pancreatic microbiota by 16s RNA-based metagenomic analysis in mice with inducible acinar transgenic expressions of KrasG12D, and age- and sex-matched control mice that were exposed to inflammatory stimuli and fecal microbiota obtained from mice with PDAC. Time- and inflammatory-dependent stool and pancreatic bacterial composition alterations and stool alpha microbiota diversity reduction were observed only in mice with a Kras mutation that developed advanced pancreatic changes. Stool Actinobacteriota abundance and pancreatic Actinobacteriota and Bifidobacterium abundances increased. In contrast, stool abundance of Firmicutes, Verrucomicrobiota, Spirochaetota, Desulfobacterota, Butyricicoccus, Roseburia, Lachnospiraceae A2, Lachnospiraceae unclassified, and Oscillospiraceae unclassified decreased, and pancreatic detection of Alloprevotella and Oscillospiraceae uncultured was not observed. Furthermore, FMT accelerated tumorigenesis, gradually decreased the stool alpha diversity, and changed the pancreatic and stool microbial composition in mice with a Kras mutation. Specifically, the abundance of Actinobacteriota, Bifidobacterium and Faecalibaculum increased, while the abundance of genera such as Lachnospiraceace A2 and ASF356, Desulfovibrionaceace uncultured, and Roseburia has decreased. In conclusion, pancreatic carcinogenesis in the presence of an oncogenic Kras mutation stimulated by chronic inflammation and FMT dynamically changes the stool and pancreas microbiota. In particular, a decrease in stool microbiota diversity and abundance of bacteria known to be involved in short-fatty acids production were observed. PDAC mouse model can be used for further research on microbiota–PDAC interactions and towards more personalized and effective cancer therapies. Full article
(This article belongs to the Section Tissues and Organs)
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15 pages, 1293 KiB  
Article
Distribution of EGFR and KRAS Mutations in Patients with Surgically Resected Non-Small Cell Lung Cancer from Southern Italy: Real-Life Data from a Single Institution and Literature Review
by Michele Piazzolla, Paola Parente, Flavia Centra, Federico Pio Fabrizio, Marco Donatello Delcuratolo, Antonella Centonza, Concetta Martina Di Micco, Mario Mastroianno, Francesco Delli Muti, Fabiola Fiordelisi, Gianmaria Ferretti, Paolo Graziano and Lucia Anna Muscarella
Cancers 2025, 17(5), 730; https://doi.org/10.3390/cancers17050730 - 21 Feb 2025
Viewed by 1406
Abstract
Background/Objectives: The identification of driver mutations in NSCLC such as those in the EGFR and KRAS genes has revolutionized the understanding and management of many lung cancer patients and has opened up a new scenario in the early disease stages in terms of [...] Read more.
Background/Objectives: The identification of driver mutations in NSCLC such as those in the EGFR and KRAS genes has revolutionized the understanding and management of many lung cancer patients and has opened up a new scenario in the early disease stages in terms of therapeutic options (EGFR) and prognosis (KRAS). Data on prevalence rates and disease stage distributions of EGFR and KRAS mutations in surgically resected NSCLC are growing, but in Southern Italy, estimation is limited, since upfront EGFR testing in early-stage adenocarcinoma has been only recently introduced according to the current guidelines in clinical practice, whereas KRAS screening is usually uninvestigated in resected NSCLC. In this real-life study of a single institution in the Apulia Region, we provide an overview of the epidemiological distribution of EGFR and KRAS mutations in patients in Southern Italy with resected NSCLC, highlighting their prevalence, clinical significance, and correlation with demographic and pathological factors. A literature review was also performed to compare our findings with the most recent available data from the screening of Italian cohorts of advanced and surgically resected NSCLC patients. Methods: Data from 149 patients coming from Southern Italy with surgically resected NSCLC were retrospectively collected over a period of 16 years. EGFR and KRAS mutation screenings were performed and correlated with clinical and pathological data. Results: In total, 24 out of 149 NSCLC (16%) patients harbored an EGFR mutation. Exon 19 deletions and missense p.L858R mutations of the EGFR gene have quite similar frequencies (46%) and were more observed in never smokers (p < 0.001) and female (p < 0.001) patients with the adenocarcinoma histotype. KRAS gene mutations were detected in 31.5% of cases, with missense p.G12C (32%), p.G12V (28%), and p.G12D (17%) mutations as the most frequent ones. Neither EGFR nor KRAS mutational status were found to impact overall survival (OS) in our study cohort. Conclusions: Our findings improve the understanding of lung cancer genetics in a small and homogeneous area of Southern Italy and guide future research. The EGFR and KRAS mutations in NSCLC resected patients from Southern Italy showed a global similar incidence compared to other recently described Italian cohorts of advanced and early-stage NSCLC, with a higher frequency of exon19 EGFR deletions. No prognostic impact was observed for both EGFR and KRAS status, but additional investigations on a larger cohort are needed. Full article
(This article belongs to the Special Issue Modern Surgical Treatments for Thoracic Malignancies)
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23 pages, 1072 KiB  
Review
Recent Anti-KRASG12D Therapies: A “Possible Impossibility” for Pancreatic Ductal Adenocarcinoma
by Navid Sobhani, Matteo Pittacolo, Alberto D’Angelo and Giovanni Marchegiani
Cancers 2025, 17(4), 704; https://doi.org/10.3390/cancers17040704 - 19 Feb 2025
Cited by 2 | Viewed by 4882
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. Results: The most common KRAS mutation is KRASG12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T cell receptors, and therapeutic vaccines. Conclusions: This comprehensive review summarizes current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials. Full article
(This article belongs to the Section Cancer Therapy)
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21 pages, 1260 KiB  
Review
The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives
by Mitsunobu Takeda, Shoma Yoshida, Takuya Inoue, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki and Hidetoshi Eguchi
Cancers 2025, 17(3), 428; https://doi.org/10.3390/cancers17030428 - 27 Jan 2025
Cited by 8 | Viewed by 7866
Abstract
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30–40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS [...] Read more.
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30–40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival. Full article
(This article belongs to the Special Issue Significance of KRAS Gene Mutations in Colorectal Cancer)
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13 pages, 1991 KiB  
Article
Outcomes of Broader Genomic Profiling in Metastatic Colorectal Cancer: A Portuguese Cohort Study
by Ricardo Roque, Rita Santos, Luís Guilherme Santos, Rita Coelho, Isabel Fernandes, Gonçalo Cunha, Marta Gonçalves, Teresa Fraga, Judy Paulo and Nuno Bonito
DNA 2025, 5(1), 4; https://doi.org/10.3390/dna5010004 - 14 Jan 2025
Cited by 1 | Viewed by 1503
Abstract
Background: Colorectal cancer (CRC) is the third most diagnosed cancer globally and the second leading cause of cancer-related deaths. Despite advancements, metastatic CRC (mCRC) has a five-year survival rate below 20%. Next-generation sequencing (NGS) is recommended nowadays to guide mCRC treatment; however, its [...] Read more.
Background: Colorectal cancer (CRC) is the third most diagnosed cancer globally and the second leading cause of cancer-related deaths. Despite advancements, metastatic CRC (mCRC) has a five-year survival rate below 20%. Next-generation sequencing (NGS) is recommended nowadays to guide mCRC treatment; however, its clinical utility when compared with traditional molecular testing in mCRC is debated due to limited survival improvement and cost-effectiveness concerns. Methods: This retrospective study included mCRC patients (≥18 years) treated at a single oncology centre who underwent NGS during treatment planning. Tumour samples were analysed using either a 52-gene Oncomine™ Focus Assay or a 500+-gene Oncomine™ Comprehensive Assay Plus. Variants were classified by clinical significance (ESMO ESCAT) and potential benefit (ESMO-MCBS and OncoKBTM). The Mann–Whitney and Chi square tests were used to compare characteristics of different groups, with significance at p < 0.05. Results: Eighty-six metastatic colorectal cancer (mCRC) patients were analysed, all being MMR proficient. Most cases (73.3%) underwent sequencing at diagnosis of metastatic disease, using primary tumour samples (74.4%) and a focused NGS assay (75.6%). A total of 206 somatic variants were detected in 86.0% of patients, 31.1% of which were classified as clinically significant, predominantly KRAS mutations (76.6%), with G12D and G12V variants as the most frequent. Among 33.7% RAS/BRAF wild-type patients, 65.5% received anti-EGFR therapies. Eleven patients (12.8%) had other actionable variants which were ESCAT level I-II, including four identified as TMB-high, four KRAS G12C, two BRAF V600E, and one HER2 amplification. Four received therapies classified as OncoKbTM level 1–2 and ESMO-MCBS score 4, leading to disease control in three cases. Conclusions: NGS enables the detection of rare variants, supports personalised treatments, and expands therapeutic options. As new drugs emerge and genomic data integration improves, NGS is poised to enhance real-world mCRC management. Full article
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