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.
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The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. ...However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.
Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over ...90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.
Raziskava korozijskih uravnav v Sloveniji podaja sistematično klasifikacijo korozijskih uravnav na podlagi njihovih geoloških in morfoloških značilnosti. Klasifikacija jih združuje v štiri ...kategorije: kraški ravnik, suho kraško polje, robna uravnava kontaktnega krasa in robna uravnava fluviokrasa. Kraški ravniki so največji in nastanejo z denudacijo v stabilnih tektonskih in hidrogeoloških razmerah. Suha kraška polja so zaprte živoskalne kotanje le mestoma prekrite s sedimenti. Robne uravnave kontaktnega krasa so nastale na stiku kraških in nekraških kamnin. Robne uravnave fluviokrasa so nastale z večfaznim razvojem kraških polj zaradi tektonske dejavnosti. Ta raziskava prispeva k boljšemu razumevanju korozijskih uravnav in lahko pomaga pri njihovi identifikaciji in upravljanju v kraških območij.
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•GTF3C6 is upregulated in LUAD tissues, LSL-KrasG12D/+;LSL-p53−/− LUAD mouse models and LUAD organoid.•Upregulation of GTF3C6 is associated with an unfavorable clinical prognosis in ...LUAD.•GTF3C6 is driven by KRAS/PI3K axis in LUAD.•GTF3C6 promotes anchorage-independent proliferation, migration, and invasion of LUAD cells via FAK pathway.
Effective targeting drugs for KRAS mutation-mediated Lung Adenocarcinoma (LUAD) are currently are limited.
Investigating and intervening in the downstream key target genes of KRAS is crucial for clinically managing KRAS mutant-driven LUAD. GTF3C6, a newly identified member of the general transcription factor III (GTF3) family, plays a role in the transcription of RNA polymerase III (pol III)-dependent genes. However, its involvement in cancer remains unexplored.
This study examined the expression, roles, and potential molecular mechanisms of GTF3C6 in LUAD tissues, LSL-KrasG12D/+;LSL-p53−/− LUAD mouse models, and LUAD patients-derived organoid using Western blot, qRT-PCR, immunofluorescence, immunohistochemistry, and gene manipulation assays.
We present the first evidence that GTF3C6 is highly expressed in LUAD tissues, LSL-KrasG12D/+;LSL-p53−/− LUAD mouse models, and LUAD organoids, correlating with poor clinical prognosis. Furthermore, GTF3C6 was found to promote anchorage-independent proliferation, migration, and invasion of LUAD cells. Mechanistically, KRAS mutation drives GTF3C6 expression through the PI3K pathway, and GTF3C6 knockdown reverses the malignant phenotype of KRAS mutation-driven LUAD cells. Additionally, the FAK pathway emerged as a crucial downstream signaling pathway through which GTF3C6 mediates the malignant phenotype of LUAD. Finally, GTF3C6 knockdown suppresses LUAD organoid formation and inhibits tumor growth in vivo.
Our findings demonstrate that GTF3C6, driven by KRAS mutation, promotes LUAD development by regulating FAK phosphorylation, suggesting its potential as a biomarker and therapeutic target in KRAS mutant-driven LUAD.
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations ...observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
•Better understanding of RAS signaling has led to the development of promising directly blocking compounds in KRAS-mutant tumors.•New drug candidates take advantage of the increased knowledge of the KRAS mutation complex and relevant protein structures.•Increasing evidence continues to demonstrate the genomic heterogeneity in KRAS-mutated NSCLC.•Current efforts include understanding and overcoming resistance after treatment with KRASG12C inhibitors.
•CRISP prospectively collected real-world data on advanced NSCLC and KRAS mutations.•Of 1039 patients, 39.5 % had KRAS mutations, 38.9 % of these were KRAS G12C-mutated.•KRAS G12C-mutated advanced ...NSCLC has poor outcome under current standard therapy.•Valuable historical control for upcoming clinical studies on KRAS-inhibitors.
After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany.
A total of 1039 patients with advanced KRAS-mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations.
Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPS > 50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPS > 50 % vs. TPS < 1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26−0.60, p=<0.001). There were no differences in clinical outcome between KRAS wildtype, G12C or non-G12C mutations and KRAS mutational status was not prognostic in the model.
Here we describe the so far largest prospectively recruited cohort of patients with advanced NSCLC and KRAS mutations, with special focus on the G12C mutation. These data constitute an extremely valuable historical control for upcoming clinical studies that employ KRAS inhibitors.
Patient-derived organoids (PDOs) are promising tumor avatars that could enable ex vivo drug tests to personalize patients’ treatments in the frame of functional precision oncology. However, clinical ...evidence remains scarce. This study aims to evaluate whether PDOs can be implemented in clinical practice to benefit patients with advanced refractory pancreatic ductal adenocarcinoma (PDAC).
During 2021 to 2022, 87 patients were prospectively enrolled in an institutional review board–approved protocol. Inclusion criteria were histologically confirmed PDAC with the tumor site accessible. A panel of 25 approved antitumor therapies (chemogram) was tested and compared to patient responses to assess PDO predictive values and map the drug sensitivity landscape in PDAC.
Fifty-four PDOs were generated from 87 pretreated patients (take-on rate, 62%). The main PDO mutations were KRAS (96%), TP53 (88%), and CDKN2A/B (22%), with a 91% concordance rate with their tumor of origin. The mean turnaround time to chemogram was 6.8 weeks. In 91% of cases, ≥1 hit was identified (gemcitabine (n = 20 of 54), docetaxel (n = 18 of 54), and vinorelbine (n = 17 of 54), with a median of 3 hits/patient (range, 0–12). Our cohort included 34 evaluable patients with full clinical follow-up. We report a chemogram sensitivity of 83.3% and specificity of 92.9%. The overall response rate and progression-free survival were higher when patients received a hit treatment as compared to patients who received a nonhit drug (as part of routine management). Finally, we leveraged our PDO collection as a platform for drug validation and combo identification. We tested anti-KRASG12D (MRTX1133), alone or combined, and identified a specific synergy with anti-EGFR therapies in KRASG12D variants.
We report the largest prospective study aiming at implementing PDO-based functional precision oncology and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. Although this remains to be confirmed in interventional precision oncology trials, PDO collection already provides powerful opportunities for drugs and combinatorial treatment development.
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In a large prospective study that aims to implement organoid-based functional precision medicine for pancreatic cancer, we identified, in a clinically relevant turnaround time, at least 1 putative hit in 91% of cases, with potential survival benefits.
Circular RNAs (circRNAs) are stable non-coding RNAs characterized by the absence of the conventional 5′ cap and 3′ polyadenylated tail structure. Its involvement in various aspects of cancers ...underscores its significance in oncology. Elevated expression of circ_0000620 was observed in both lung adenocarcinoma (LUAD) tissues and cell lines. In vitro, experiments demonstrated that the downregulation of circ_0000620 increased cisplatin sensitivity and promoted cell apoptosis while suppressing malignant characteristics such as cell migration and proliferation. Further investigation into the mechanism underlying the increased expression of circ_0000620 revealed that Methyltransferase 3, N6-Adenosine-Methyltransferase Complex Catalytic Subunit (METTL3) mediates the m6A methylation modification of circ_0000620, thereby promoting its stability and expression. Furthermore, circ_0000620 modulates the miR-216b-5p/KRAS axis to influence apoptosis and cisplatin sensitivity in both A549 and H1299 cell lines. These findings were corroborated by in vivo nude mouse experiments, which showed that knockdown of circ_0000620 inhibited tumor growth and proliferation. In summary, METTL3 plays a role in regulating the stability of circ_0000620 expression, and circ_0000620 exerts its effects on LUAD apoptosis and cisplatin sensitivity through the miR-216b-5p/KRAS signaling pathway.
•METTL3 regulates circ_0000620 stability and expression via m6A modification in lung adenocarcinoma.•circ_0000620 acts as a miR-216b-5p sponge in lung adenocarcinoma•circ_0000620 affects KRAS expression and cisplatin response.•The METTL3/circ_0000620/miR-216b-5p/KRAS axis influences cisplatin sensitivity.•Targeting this pathway may overcome cisplatin resistance in lung adenocarcinoma.
With recent advances proving that effective inhibition of KRAS is possible, there have been significant efforts made to develop inhibitors of specific mutant alleles. Here we describe a detailed ...protocol that employs homogeneous time-resolved fluorescence (HTRF) to identify compounds acting on KRAS signaling in malignant cell lines. This method allows for high-throughput, cell-based screens of large compound libraries for the development of RAS-targeted therapeutics.
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