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Search Results (921)

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14 pages, 848 KiB  
Review
A Narrative Review of RAS Mutations in Early-Stage Colorectal Cancer: Mechanisms and Clinical Implications
by Hasan Cagri Yildirim, Damla Gunenc, Elvina Almuradova, Osman Sutcuoglu and Suayib Yalcin
Medicina 2025, 61(3), 408; https://doi.org/10.3390/medicina61030408 - 26 Feb 2025
Viewed by 59
Abstract
Colorectal cancer (CRC) is the third-most common cancer globally and a leading cause of cancer-related deaths. While the prognostic and predictive roles of RAS mutations in advanced CRC are well-established, their significance in early-stage CRC remains a topic of debate. Studies have been [...] Read more.
Colorectal cancer (CRC) is the third-most common cancer globally and a leading cause of cancer-related deaths. While the prognostic and predictive roles of RAS mutations in advanced CRC are well-established, their significance in early-stage CRC remains a topic of debate. Studies have been conducted for many years on clinical and pathological parameters that may be associated with RAS mutation, and there are inconsistent results in this regard. Currently, the only biomarker used in early-stage CRC is microsatellite status. KRAS mutations are detected in 40–50% of patients with colorectal cancer. RAS activating mutations cause loss of EGFR regulation by acting on the RAS/RAF/MAPK signaling pathways. In advanced colorectal cancer, these mechanisms cause a decrease in the effectiveness of EGFR inhibitors. However, studies on patients with early-stage colorectal cancer have inconsistent results. This review highlights the prognostic and clinical significance of KRAS mutations in early-stage CRC, particularly in MSS tumors. In the MSS group, KRAS mutations were associated with shorter TTR and OS compared to DWT patients. In contrast, in the MSI-H group, KRAS mutations showed no prognostic effect in TTR and OS. However. KRAS mutations were associated with shorter SAR in both MSI-H and MSS groups of patients. The findings underscore the need for routine molecular profiling, including KRAS and MSI status, to refine risk stratification and guide adjuvant therapy decisions. Further studies are warranted to explore targeted therapeutic approaches for KRAS-mutant CRC in the adjuvant setting. Full article
(This article belongs to the Section Oncology)
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15 pages, 35957 KiB  
Article
Establishment of a Novel In Vitro and In Vivo Model to Understand Molecular Carcinogenesis of Endometriosis-Related Ovarian Neoplasms
by Hasibul Islam Sohel, Tohru Kiyono, Umme Farzana Zahan, Sultana Razia, Masako Ishikawa, Hitomi Yamashita, Kosuke Kanno, Shahataj Begum Sonia, Kentaro Nakayama and Satoru Kyo
Int. J. Mol. Sci. 2025, 26(5), 1995; https://doi.org/10.3390/ijms26051995 - 25 Feb 2025
Viewed by 106
Abstract
The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This [...] Read more.
The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This study aimed to investigate the molecular carcinogenesis of ERONs using newly developed in vitro and in vivo carcinogenesis models. Epithelial cells were isolated and purified from surgically removed benign endometrioma samples, followed by immortalization by overexpressing cyclinD1/CDK4 in combination with the human TERT gene. Immortalized cells were subjected to various molecular manipulations by combining knockout or overexpression of several candidate drivers, including ARID1A, KRAS, PIK3CA, AKT, and MYC, based on previous comprehensive genome-wide studies of ERONs. These cells were then inoculated into immunocompromised mice and evaluated for malignant transformation. Inoculated cells harboring a combination of three genetic alterations successfully developed tumors with malignant features in mice, whereas those with two genetic manipulations failed to do so. Especially, ARID1A gene knockout, combined with overexpressing the KRAS oncogenic mutant allele (or overexpressing AKT) and c-Myc overexpression led to efficient tumor formation. Of note, these three combinations of genetic alterations produced tumors that histologically represented typical clear cell carcinoma in SCID mice, while the same combination led to tumors with endometrioid histology in nude mice. A combination of ARID1A mutation, KRAS mutation or AKT activation, and c-Myc overexpression were confirmed to be the main candidate drivers for the development of ERONs, as suggested by comprehensive genetic analyses of ERONs. A tumor immune microenvironment involving B-cell signaling may contribute to the diverse histological phenotypes. The present model may help to clarify the molecular mechanisms of ERON carcinogenesis and understand their histological diversity and novel molecular targets. Full article
(This article belongs to the Special Issue Molecular Genetics in Ovarian Cancer)
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32 pages, 2615 KiB  
Review
KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy
by Priyanka Uniyal, Vivek Kumar Kashyap, Tapan Behl, Deepak Parashar and Ravi Rawat
Cancers 2025, 17(5), 785; https://doi.org/10.3390/cancers17050785 - 25 Feb 2025
Viewed by 112
Abstract
The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the [...] Read more.
The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers. Full article
(This article belongs to the Special Issue Inflammation, Immunity, and Cancer Progression: 2nd Edition)
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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 244
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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13 pages, 1465 KiB  
Article
Correlation of GNAS Mutational Status with Oncologic Outcomes in Patients with Resected Intraductal Papillary Mucinous Neoplasms
by Julia Evans, Kylee Shivok, Hui Hsuan Chen, Eliyahu Gorgov, Wilbur B. Bowne, Aditi Jain, Harish Lavu, Charles J. Yeo and Avinoam Nevler
Cancers 2025, 17(4), 705; https://doi.org/10.3390/cancers17040705 - 19 Feb 2025
Viewed by 256
Abstract
Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic lesions that may progress to invasive pancreatic ductal adenocarcinoma (PDAC). IPMN-associated invasive carcinoma (iIPMN) has been associated with more favorable survival outcomes compared to non-iIPMN-derived PDAC. Here, we aim to investigate the genetic landscape [...] Read more.
Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic lesions that may progress to invasive pancreatic ductal adenocarcinoma (PDAC). IPMN-associated invasive carcinoma (iIPMN) has been associated with more favorable survival outcomes compared to non-iIPMN-derived PDAC. Here, we aim to investigate the genetic landscape of IPMNs to assess their relevance to oncologic outcomes. Methods: This retrospective study used a large single-institution prospectively maintained database. Patients who underwent curative-intent pancreatic resection between 2016 and 2022 with histologically confirmed diagnosis of IPMN were included. Demographic, pathologic, molecular, and oncologic outcome data were recorded. Kaplan–Meier survival analyses were performed. PDAC data from public genetic databases were used for mutational correlation analysis. p-value ≤ 0.05 was considered as significant. Results: A total of thirty-nine patients with resected IPMN with complete clinical and sequencing data were identified and included in the final cohort. The male-to-female distribution was 21:18, and the mean age was 70.1 ± 9.1 years. GNAS mutations occurred in 23.1% of patients, and 89.7% of patients had iIPMN. In iIPMN patients, GNAS mutation was strongly associated with improved disease-free survival: all GNAS-mutant patients survived to follow-up with significantly fewer recurrences than in GNAS wild-type (WT) patients (p = 0.013). Mutated GNAS closely co-occurred with wild-type KRAS (p < 0.001), and further analysis of large genomic PDAC datasets validated this finding (OR 3.47, p < 0.0001). Conclusions: Our study suggests prognostic value of mutational status in malignant resected IPMNs. WT GNAS, mutant P53, and mutant KRAS each correlate with recurrence and decreased survival. Further studies are required to validate these preliminary observations. Full article
(This article belongs to the Special Issue Surgical Oncology for Hepato-Pancreato-Biliary Cancer)
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23 pages, 1120 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
Viewed by 420
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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14 pages, 2327 KiB  
Article
The Prognostic Impact of Additional Molecular and Cytogenetic Abnormalities on AML Patients with NPM1- and/or FLT3-ITD Mutations Receiving Intensive Chemotherapy: Real-World Data from the Greek Registry
by Ioanna Lazana, Maria Papathanassiou, Ioannis Konstantellos, Tatiana Tzenou, Anastasia Kopsaftopoulou, Maria Liga, Vasiliki Violaki, Lydia Kyriazopoulou, Konstantinos Gkirkas, Apostolia Papalexandri, Eleni Plata, Evrydiki Michalis, Theoni Leonidopoulou, Maria Garofalaki, Anastasia Sioni, Irene Tziotziou, Chrysavgi Lalayanni, Dimitrios Kiousiafes, Theodoros P. Vassilakopoulos, Eleni Kapsali, Alexandros Spyridonidis, Ioannis Baltadakis, Maria Angelopoulou, Ioanna Sakellari and Panagiotis Tsirigotisadd Show full author list remove Hide full author list
Cancers 2025, 17(4), 667; https://doi.org/10.3390/cancers17040667 - 16 Feb 2025
Viewed by 351
Abstract
Background/Objective: The prognostic impact of additional cytogenetic aberrations and molecular abnormalities (such as MDS-related mutations, mutations in myeloid genes and the KRAS/NRAS mutations) in patients with NPM1- and/or FLT3-ITD-mutated AML remains elusive. Methods: This retrospective, multicentre study of real-world data aimed [...] Read more.
Background/Objective: The prognostic impact of additional cytogenetic aberrations and molecular abnormalities (such as MDS-related mutations, mutations in myeloid genes and the KRAS/NRAS mutations) in patients with NPM1- and/or FLT3-ITD-mutated AML remains elusive. Methods: This retrospective, multicentre study of real-world data aimed to investigate the impact of these mutations and cytogenetic abnormalities on the prognosis of patients with NPM1- and/or FLT3-ITD-mutated AML, treated with intensive chemotherapy. Results: In a cohort of 161 patients, the only parameters identified to affect the outcomes (EFS and OS) were the age of the patient, primary refractory disease, the presence of a NPM1 mutation and the use of allogenic stem cell transplantation (allo-SCT) within the first complete remission. More specifically, ages below the median conferred significantly improved outcomes, whereas primary refractory disease exhibited a negative correlation with the EFS and OS. Subsequent subgroup analysis, stratifying patients into three groups (Group 1: NPM1mutated/FLT3wt; Group 2: NPM1mutated/FLT3mutated; Group 3: NPM1wt/FLT3mutated). revealed that allo-SCT in CR1 improved the outcomes (EFS and OS) in Groups 2 and 3, but had no additional impact in Group 1. Conclusions: Age, primary refractory disease and allogenic stem cell transplantation in the first complete response were found to have a prognostic impact on outcomes, Interestingly, no significant association was detected between the poor prognostic cytogenetic abnormalities or the presence of additional mutations in myeloid genes, MDS-related genes or KRAS/NRAS genes and the outcomes in any group of patients. Full article
(This article belongs to the Section Molecular Cancer Biology)
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13 pages, 4214 KiB  
Article
Correlation of PD-L1 and HIF-1 Alpha Expression with KRAS Mutation and Clinicopathological Parameters in Non-Small Cell Lung Cancer
by Seda Er Özilhan, Safa Can Efil, Doğukan Çanakçı, Yetkin Ağaçkıran, Didem Şener Dede, Nilüfer Onak Kandemir, Mehmet Doğan, Tuba Dilay Kökenek Ünal, Merve Meryem Kıran, Serra Kayaçetin, Hilal Balta and Hayriye Tatlı Doğan
Curr. Issues Mol. Biol. 2025, 47(2), 121; https://doi.org/10.3390/cimb47020121 - 13 Feb 2025
Viewed by 424
Abstract
Background: Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung carcinomas (NSCLCs) comprising the majority of cases. Among the common driver mutations, KRAS plays a critical role in guiding treatment strategies. This study evaluates the expression of programmed [...] Read more.
Background: Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung carcinomas (NSCLCs) comprising the majority of cases. Among the common driver mutations, KRAS plays a critical role in guiding treatment strategies. This study evaluates the expression of programmed death-ligand 1 (PD-L1) and hypoxia-inducible factor 1-alpha (HIF-1α) in KRAS-mutant NSCLCs and investigates their associations with clinicopathological findings. Methods: A total of 85 cases with KRAS mutations were analyzed. Immunohistochemical staining for HIF-1α and PD-L1 was performed, and their relationships with mutation status and prognostic variables were assessed. Results: A significant correlation was identified between HIF-1α expression and PD-L1 expression in tumor cells. While the KRAS G12C mutation was not significantly associated with HIF-1α expression in tumor cells, it demonstrated a notable relationship with HIF-1α expression in the tumor microenvironment and PD-L1 expression. However, PD-L1 and HIF-1α expression did not significantly influence overall survival outcomes. Conclusions: Expression of PD-L1 was positively correlated with HIF-1α, which may provide evidence for a novel therapy targeting PD-L1 and HIF-1α in NSCLC. Further comprehensive studies are warranted to elucidate the prognostic implications of tumor–microenvironment and mutation interactions. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)
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17 pages, 548 KiB  
Article
KRAS Mutation Status in Relation to Clinicopathological Characteristics of Romanian Colorectal Cancer Patients
by Elena-Roxana Avădănei, Irina-Draga Căruntu, Irina Nucă, Raluca Anca Balan, Ludmila Lozneanu, Simona-Eliza Giusca, Diana Lavinia Pricope, Cristina Gena Dascalu and Cornelia Amalinei
Curr. Issues Mol. Biol. 2025, 47(2), 120; https://doi.org/10.3390/cimb47020120 - 12 Feb 2025
Viewed by 391
Abstract
Our study’s aim was to evaluate the clinicopathological profile of colorectal cancer (CRC) patients from North-East Romania in relation to the Kirsten rat sarcoma viral oncogene homolog (KRAS). We designed a retrospective study on 108 CRC patients using the fully automated [...] Read more.
Our study’s aim was to evaluate the clinicopathological profile of colorectal cancer (CRC) patients from North-East Romania in relation to the Kirsten rat sarcoma viral oncogene homolog (KRAS). We designed a retrospective study on 108 CRC patients using the fully automated real-time PCR-based molecular testing system, IdyllaTMKRAS Mutation Test (Biocartis, Mechelen, Belgium). Of the patients, 64 (59.3%) were men and 62 (57.4%) were older than the group average, with left bowel location in 38 cases (35.2%), adenocarcinoma NOS in 102 cases (94.4%), mixed histological pattern in 65 cases (60.2%), T3 in 60 patients (55.6%), N2 in 46 patients (42.6%), and 7–12 tumour buds registered in 58 tumours (53.7%). A total of 54 tumour samples (50%) showed KRAS mutation. Statistical comparative analyses associated KRAS mutations with the histopathological pattern (p = 0.018), tumour grade (p = 0.030), depth of invasion (pT) (p < 0.001), lymph node involvement (pN) (p < 0.001), venous vascular invasion (p = 0.048), and tumour buds’ number (p = 0.007). Our results demonstrate the relationship between KRAS mutation and clinicopathological features, with possible impact in clinical tumour stratification and therapeutic management. Full article
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15 pages, 262 KiB  
Review
Molecular Biomarkers in Borderline Ovarian Tumors: Towards Personalized Treatment and Prognostic Assessment
by Stefania Drymiotou, Efthymia Theodorou, Kathrine Sofia Rallis, Marios Nicolaides and Michail Sideris
Cancers 2025, 17(3), 545; https://doi.org/10.3390/cancers17030545 - 6 Feb 2025
Viewed by 574
Abstract
Borderline Ovarian Tumours (BOTs) are a heterogenous group of ovarian neoplasms which have increased mitotic activity but lack stromal invasion. We performed a narrative review of the literature, aiming to identify prognostic molecular biomarkers that can potentially be used for treatment personalisation. We [...] Read more.
Borderline Ovarian Tumours (BOTs) are a heterogenous group of ovarian neoplasms which have increased mitotic activity but lack stromal invasion. We performed a narrative review of the literature, aiming to identify prognostic molecular biomarkers that can potentially be used for treatment personalisation. We identified and discussed BRAF/KRAS, Cancer Antigen 125 (Ca 125), Calprotectin, p16ink4a, and Microsatellite instability (MSI) as the most studied biomarkers related to BOTs. Overall, BRAF and KRAS mutations are associated with earlier-stage and favourable prognosis; KRASmt may indicate extraovarian disease in serous BOT (sBOT). Ca125, the only currently clinically used biomarker, can be assessed pre-operatively and has an established role in post-operative surveillance, especially when it is raised pre-operatively or a high potential for malignant transformation is suspected post-operatively. p16ink4a expression trends could also indicate the malignant transformation of the tumour. Calprotectin has an inferior specificity to Ca125 and is not yet established as a biomarker, whilst there is very limited evidence available for MSI. As new evidence is coming along with artificial intelligence platforms, these biomarkers can be integrated and used towards the development of a precision model for treatment stratification and counselling in women diagnosed with BOTs. Full article
(This article belongs to the Special Issue Diagnostic Biomarkers in Cancers Study)
23 pages, 2649 KiB  
Perspective
Colorectal Cancer: Current and Future Therapeutic Approaches and Related Technologies Addressing Multidrug Strategies Against Multiple Level Resistance Mechanisms
by Marianna Puzzo, Marzia De Santo, Catia Morelli, Antonella Leggio, Stefania Catalano and Luigi Pasqua
Int. J. Mol. Sci. 2025, 26(3), 1313; https://doi.org/10.3390/ijms26031313 - 4 Feb 2025
Viewed by 802
Abstract
Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future [...] Read more.
Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission. Full article
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15 pages, 2774 KiB  
Article
Knockout of p21-Activated Kinase 4 Stimulates MHC I Expression of Pancreatic Cancer Cells via an Autophagy-Independent Pathway
by Yi Ma, Chelsea Dumesny, Li Dong, Ching-Seng Ang, Mehrdad Nikfarjam and Hong He
Cancers 2025, 17(3), 511; https://doi.org/10.3390/cancers17030511 - 3 Feb 2025
Viewed by 885
Abstract
Background/Objectives: Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% of cases. p21-activated kinases (PAKs) act downstream of KRAS and are involved in tumorigenesis. The inhibition of PAK4 suppresses PDA by stimulating the tumor [...] Read more.
Background/Objectives: Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% of cases. p21-activated kinases (PAKs) act downstream of KRAS and are involved in tumorigenesis. The inhibition of PAK4 suppresses PDA by stimulating the tumor infiltration of cytotoxic T cells. The major histocompatibility complex class I (MHC I) is a key in presenting antigens to cytotoxic T cells. MHC I degradation via autophagy promotes the immune evasion of pancreatic cancer. We investigated the effect of PAK4 inhibition on MHC I expression and autophagy. Methods: In this study, using proteomic analysis, fluorescence-activated cell sorting (FACS), and immunoblotting, we examined the effect of PAK4 knockout (KO) in human PDA cells on the expression of MHC I and autophagy to identify the mechanism involved in the stimulation of cytotoxic T cells by PAK4 inhibition. Results: We found that PAK4 KO increased MHC I expression in two human PDA cell lines: MiaPaCa-2 and PANC-1. PAK4 KO also increased cancer cell autophagy. However, the inhibition of autophagy by chloroquine (CQ) did not affect the effect of PAK4 KO on apoptosis and cell death. More importantly, the inhibition of autophagy by CQ did not alter the expression of MHC I stimulated by PAK4 KO, indicating that PAK4 KO stimulated MHC I expression via an autophagy-independent pathway. Conclusions: We identified a role of PAK4 in MHC I expression by PDA cells, which is independent of autophagy. Full article
(This article belongs to the Section Molecular Cancer Biology)
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16 pages, 3070 KiB  
Article
Immunotherapy Improves Clinical Outcome in Kirsten Rat Sarcoma Virus-Mutated Patients with Unresectable Non-Small Cell Lung Cancer Stage III: A Subcohort Analysis of the Austrian Radio-Oncological Lung Cancer Study Association Registry (ALLSTAR)
by Elvis Ruznic, Marisa Klebermass, Barbara Zellinger, Brigitte Langer, Brane Grambozov, Ayurzana Purevdorj, Josef Karner, Georg Gruber, Markus Stana, Danijela Minasch, Karoline Kirchhammer, Claudia Steffal, Heidi Stranzl, Raphaela Moosbrugger, Petra Feurstein, Karin Dieckmann and Franz Zehentmayr
J. Clin. Med. 2025, 14(3), 945; https://doi.org/10.3390/jcm14030945 - 1 Feb 2025
Viewed by 904
Abstract
Background/Objectives: Current evidence suggests that patients with unresectable non-small cell lung cancer (NSCLC) whose tumours harbour driver mutations do not benefit from immune checkpoint inhibition. Kirsten rat sarcoma virus mutations (KRASmts), however, seem to be the exceptions to the rule. To this [...] Read more.
Background/Objectives: Current evidence suggests that patients with unresectable non-small cell lung cancer (NSCLC) whose tumours harbour driver mutations do not benefit from immune checkpoint inhibition. Kirsten rat sarcoma virus mutations (KRASmts), however, seem to be the exceptions to the rule. To this end, we compared KRASmt patients who were treated with immunotherapy to those without. Methods: ALLSTAR is a nationwide registry for patients with histologically verified non-operable NSCLC aged 18 or older having a curative treatment option. This report presents a subcohort of KRASmt patients who were recruited between 2020/03 and 2023/04. The diagnostic work-up included 18F-FDG-PET-CT scan and contrast-enhanced cranial CT or—preferably—MRI. Patients were treated with chemoradiotherapy (CRT) either followed by immune checkpoint inhibition (ICI) or not. Results: Thirty-two KRASmt patients with a median follow-up of 25.9 months were included in this analysis. After CRT, 27/32 (84%) patients received ICI. The 2-year overall survival rate in KRASmt patients who received immunotherapy was significantly better compared to those without ICI (N = 32; 84% versus 20%; p < 0.001). Likewise, the 2-year progression-free-survival with immunotherapy was also significantly better than in those without ICI (N = 32; 75% versus 20%; p < 0.001). Of the 12/32 patients (38%) who had received radiation doses > 66 Gy, none had a locoregional relapse, whereas in the other 20 patients, 5 (25%) events occurred (p-value = 0.116). Conclusions: Since KRASmt patients could benefit from ICI treatment, immunotherapy should be offered to these patients, similar to those without actionable genetic drivers. Additionally, radiation dose escalation > 66 Gy may also improve locoregional control in this subset of patients. Full article
(This article belongs to the Special Issue Latest Advances in Thoracic Surgery)
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12 pages, 2592 KiB  
Article
Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC
by Soumavo Mukherjee, Dhananjay Suresh, Ajit Zambre, Sairam Yadavilli, Shreya Ghoshdastidar, Anandhi Upendran and Raghuraman Kannan
Cancers 2025, 17(3), 490; https://doi.org/10.3390/cancers17030490 - 1 Feb 2025
Viewed by 736
Abstract
Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through [...] Read more.
Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through the AXL–SRC–Akt axis. In this study, we identify AXL as the bypass resistant gene and investigate its role with KRAS and SRC activity. Methods: In this study, we use Dasatinib and SGI-7079 to co-inhibit SRC and AXL respectively. In vitro studies were conducted using four cell lines, and AXL suppression was achieved using siRNA and in CRISPR-Cas9 mediated knockout models. Subsequently, we studied gene-protein expression analysis using Western blot, apoptotic markers using a cytochrome release assay and cytotoxicity using an MTT assay. A549 xenografts were studied for in vivo validation of our proposed hypothesis. Results: The results suggest that dual inhibition of AXL and SRC significantly reversed this resistance, both in in vivo and in vitro studies. Conclusions: Co-inhibition of AXL and SRC synergistically reduced KRAS activity and induced apoptosis in NSCLC. Full article
(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)
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Article
Precision Oncology in Clinical Practice: Two Years of Comprehensive Genomic Profiling in Croatia
by Dora Čerina Pavlinović, Jelena Šuto Pavičić, Antonela Njavro, Nikša Librenjak, Ilijan Tomaš, Robert Šeparović, Stjepko Pleština, Žarko Bajić, Natalija Dedić Plavetić and Eduard Vrdoljak
J. Pers. Med. 2025, 15(2), 59; https://doi.org/10.3390/jpm15020059 - 31 Jan 2025
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Abstract
Background: The widespread adoption of precision medicine in routine cancer care remains a critical challenge, even as advanced technologies expand and personalized therapies demonstrate remarkable success in certain cancer types. While breakthrough innovations in targeted treatments have revolutionized outcomes for specific cancers, translating [...] Read more.
Background: The widespread adoption of precision medicine in routine cancer care remains a critical challenge, even as advanced technologies expand and personalized therapies demonstrate remarkable success in certain cancer types. While breakthrough innovations in targeted treatments have revolutionized outcomes for specific cancers, translating these scientific advances into standard clinical practice continues to be an evolving and complex endeavor. Croatia has a nationwide project of precision oncology through the comprehensive genomic profiling (CGP) analysis. Since collecting and analyzing real-world data is crucial for clinical research and defining the value of CGP in precision oncology, we aimed to present the data from everyday clinical practice given the opportunities and challenges we faced. Methods: This was a retrospective observational study conducted at the national level in all patients whose tumor samples were subjected to CGP between 1 January 2020 and 31 December 2021. Results: In total, 481 patients with CGP results were included in this study. Gastrointestinal and reproductive malignancies were the most common, accounting for 29.1% and 28.9% of all tested tumors, respectively. Specifically, colorectal tumors made up 19.1% of cases, while uterine tumors represented 11.2%. At least one clinically relevant genomic alteration was found in 76.7% of patients, with the KRAS mutation (27.2%) being the most common. During the two-year study period, 26,709 individuals lost their lives to cancer in Croatia. Combining this with the CGP selection criteria valid at the time, there was an estimated population of approximately 13,350 potentially eligible patients for the CGP analysis, meaning that only 3.6% of potentially eligible patients were tested. Conclusions: The analysis identified clinically actionable genomic alterations in approximately 80% of the evaluated patients, suggesting they could be candidates for targeted therapeutic interventions. The adoption of CGP remains limited, with estimates indicating that under 5% of metastatic cancer patients received testing in the initial two-year implementation period, despite established national insurance coverage guidelines. This low utilization rate suggests a significant gap in access to genomic testing, leaving many eligible cancer patients without the potential benefits of this diagnostic approach. Full article
(This article belongs to the Section Personalized Therapy and Drug Delivery)
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