Oncogene In Cancer Research Articles

Cortactin contributes to the tumorigenesis of gastric cancer by activating ERK/MMP pathway

Gastric cancer is a malignant tumor with high mortality and high incidence. This study aims to explore the function and molecular mechanism of Cortactin on gastric cancer progression in vitro and in vivo. A bioinformatics analysis from TCGA displayed that Cortactin was highly expressed in gastric cancer samples, and patients with a high Cortactin level had a worse survival rate. Subsequently, we investigated the specific mechanism of action of A in gastric cancer by collecting patient samples for immunohistochemistry, WB, qRT-PCR, cell transfection, cell invasion and metastasis, and constructing tumor xenografts in nude mice. Overexpression of Cortactin inhibited apoptosis and enhanced cellular proliferation and mobility in AGS cells, while those activities were reversed by the knockdown of MMP2 or MMP9. Conversely, the deletion of Cortactin induced apoptosis and suppressed cell growth and metastasis in SGC7901 cells, whereas those behaviors were inhibited by overexpression of MMP2 or MMP9. Additionally, the ERK pathway was activated by Cortactin upregulation. In vivo studies presented that overexpression of Cortactin promoted tumor growth, increased Ki67 expression, and reduced caspase 3 expression, which was reversed by ERK inhibitor treatment. In conclusion, Cortactin acted as an oncogene in gastric cancer and exerted its function by ERK/MMP2/MMP9 signaling pathway.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Inhalable siRNA Nanoparticles for Enhanced Tumor-Targeting Treatment of KRAS-Mutant Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma (KRAS) is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of KRAS-mutant NSCLC and other respiratory diseases.

PSRC1 Regulated by DNA Methylation Is a Novel Target for LGG Immunotherapy.

Proline and serine-rich coiled-coil 1 (PSRC1) has been reported to function as an oncogene in several cancers by regulating mitosis, while there are few reports on the role of PSRC1 in lower-grade glioma (LGG). Thus, this study collected 22 samples and 1126 samples from our institution and several databases, respectively, to explore the function of PSRC1 in LGG. First, the analysis of clinical characteristics showed that PSRC1 was always highly expressed in more malignant clinical characteristics of LGG, such as higher WHO grade, recurrence type, and IDH wild type. Second, the prognosis analysis revealed that the high expression of PSRC1 was an independent risk factor contributing to the shorter overall survival of LGG patients. Third, the analysis of DNA methylation showed that the expression of PSRC1 was associated with its 8 DNA methylation sites, overall negatively regulated by its DNA methylation level in LGG. Fourth, the analysis of immune correlation revealed that the expression of PSRC1 was positively correlated with the infiltration of 6 immune cells and the expression of 4 well-known immune checkpoints in LGG, respectively. Finally, co-expression analysis and KEGG analysis showed the 10 genes most related to PSRC1 and the signaling pathways involved by PSRC1 in LGG, respectively, such as MAPK signaling pathway and focal adhesion. In conclusion, this study identified the pathogenic role of PSRC1 in the pathological progression of LGG, expanding the molecular understanding of PSRC1, and provided a biomarker and potential immunotherapeutic target for the treatment of LGG.

WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia.

WDR54 has been recently identified as a novel oncogene in colorectal and bladder cancers. However, the expression and function of WDR54 in T-cell acute lymphoblastic leukemia (T-ALL) were not reported. In this study, we investigated the expression of WDR54 in T-ALL, as well as its function in T-ALL pathogenesis using cell lines and T-ALL xenograft. Bioinformatics analysis indicated high mRNA expression of WDR54 in T-ALL. We further confirmed that the expression of WDR54 was significantly elevated in T-ALL. Depletion of WDR54 dramatically inhibited cell viability and induced apoptosis and cell cycle arrest at S phase in T-ALL cells in vitro. Moreover, knockdown of WDR54 impeded the process of leukemogenesis in a Jurkat xenograft model in vivo. Mechanistically, the expression of PDPK1, phospho-AKT (p-AKT), total AKT, phospho-ERK (p-ERK), Bcl-2 and Bcl-xL were downregulated, while cleaved caspase-3 and cleaved caspase-9 were upregulated in T-ALL cells with WDR54 knockdown. Additionally, RNA-seq analysis indicated that WDR54 might regulate the expression of some oncogenic genes involved in multiple signaling pathways. Taken together, these findings suggest that WDR54 may be involved in the pathogenesis of T-ALL and serve as a potential therapeutic target for the treatment of T-ALL.

RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming.

Since the discovery of oncogenes in the 1970s, cancer doctors and researchers alike have understood the promise of discovering drugs to block the dominantly acting function of mutated signaling proteins in cancer. This promise was delivered, first slowly, with early signals inhibiting HER2 and BCR-Abl in the 1990s and 2000s, and then quickly, with kinase inhibitors being approved hand over fist in non-small cell lung cancer, melanoma, and many other malignancies. The RAS proteins, however, remained recalcitrant to chemical inhibition for decades, despite being, by far, the most frequently mutated oncogenes in cancers of all types. Nowhere was this deficit more palpable than in pancreatic ductal adenocarcinoma (PDA), where > 90% of cases are driven by single nucleotide substitutions at a single codon of the KRAS gene. The ice began to crack in 2012 when Ostrem and colleagues (Nature 503(7477): 548-551, 2013) synthesized the first KRAS G12C inhibitors, which covalently bind to GDP-bound G12C-mutated KRAS and lock the oncoprotein in its inactive state. In the last decade, the scientific community has established a new foundation on this and other druggable pockets in mutant KRAS. Here we provide an up-to-date overview of drugs targeting KRAS and other molecular targets in pancreatic cancer.

Exosome-derived ANXA9 functions as an oncogene in breast cancer.

Breast cancer (BCA) is one of the most prevalent cancers among women. Emerging evidence has revealed that Annexin A-9 (ANXA9) plays a crucial function in the development of some cancers. Notably, ANXA9 has been reported to be a new prognostic biomarker for gastric and colorectal cancers. However, its expression and biological function in BCA have not yet been investigated. Using online bioinformatics tools such as TIMER, GEPIA, HPA, and UALCAN, we predicted ANXA9 expression and its correlation with the clinicopathological characteristics of BCA patients. RT-qPCR and western blot were utilized to measure ANXA9 mRNA and ANXA9 protein expression in BCA patient tissues and cells. BCA-derived exosomes were identified by transmission electron microscopy. Functional assays were employed to evaluate the biological role of ANXA9 in BCA cell proliferation, migration, invasion, and apoptosis. A tumor xenograft in vivo model was utilized to assess the role of ANXA9 in tumor growth in mice. Bioinformatics and functional screening analysis revealed that ANXA9 was highly expressed in BCA patient tissues, with median ANXA9 expression 1.5- to 2-fold higher than in normal tissues (p < 0.05). RT-qPCR confirmed that ANXA9 expression in BCA tissues was around 1.5-fold higher than the adjacent normal tissues (p < 0.001). ANXA9 expression in different subtypes of BCA also showed a difference, and ANXA9 was found to be mostly significantly upregulated in luminal BCA relative to normal tissues or other histological subtypes (p < 0.001). Moreover, ANXA9 expression was elevated in different races, ages, clinical stages, node metastasis status, and menopause status groups relative to the normal group (p < 0.001). Furthermore, ANXA9 was found to be secreted by BCA tissue-derived exosomes and its expression was upregulated 1- to 7-fold in BCA cells treated with exosomes (p < 0.001), while its expression in MCF10A cells was not significantly altered by treatment with exosomes (p > 0.05). ANXA9 silencing induced a significant decrease of around 30% in the colony number of BCA cells (p < 0.01). The number of migrated and invaded BCA cells also decreased by around 65 and 68%, respectively, after silencing ANXA9 (p < 0.01). Tumor size was significantly reduced (nearly half) in the LV-sh-ANXA9 group relative to the LV-NC group in the xenograft model (p < 0.01), suggesting that ANXA9 silencing repressed tumor progression in BCA progression in vitro and in vivo. In conclusion, exosome-derived ANXA9 functions as an oncogene that facilitates the proliferation, migration, and invasiveness of BCA cells and enhances tumor growth in BCA development, which may provide a new prognostic and therapeutic biomarker for BCA patients.

CUL4A silencing attenuates cervical carcinogenesis and improves Cisplatin sensitivity.

CUL4A is an ubiquitin ligase deregulated in numerous pathologies including cancer and even hijacked by viruses for facilitating their survival and propagation. However, its role in Human papilloma virus (HPV)-mediated cervical carcinogenesis remains elusive. The UALCAN and GEPIA datasets were analyzed to ascertain the transcript levels of CUL4A in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients. Subsequently, various biochemical assays were employed to explore the functional contribution of CUL4A in cervical carcinogenesis and to shed some light on its involvement in Cisplatin resistance in cervical cancer. Our UALCAN and GEPIA datasets analyses reveal elevated CUL4A transcript levels in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients that correlate with adverse clinicopathological parameters such as tumor stage and lymph node metastasis. Kaplan-Meier plot and GEPIA assessment depict poor prognosis of CESC patients having high CUL4A expression. Varied biochemical assays illustrate that CUL4A inhibition severely curtails hallmark malignant properties such as cellular proliferation, migration, and invasionof cervical cancer cells. We also show that CUL4A knockdown in HeLa cells causes increased susceptibility and better apoptotic induction toward Cisplatin, a mainstay drug used in cervical cancer treatment. More interestingly, we find reversion of Cisplatin-resistant phenotype of HeLa cells and an augmented cytotoxicity towards the platinum compound upon CUL4A downregulation. Taken together, our study underscores CUL4A as a cervical cancer oncogene and illustrates its potential as a prognosis indicator. Our investigation provides a novel avenue in improving current anti-cervical cancer therapy and overcoming the bottle-neck of Cisplatin resistance.

Identification of novel oncogenes in oral cancer among elderly nonsmokers.

In recent years, an increase in oral cancer among elderly nonsmokers has been noted. The aim of this study was to identify novel oncogenes in oral cancer in older nonsmokers. Whole-exome sequencing (WES) data from 324 oral cancer patients were obtained from The Cancer Genome Atlas. Single nucleotide variants (SNVs) and insertions/deletions (INDELs) were extracted from the WES data of older patients. Fisher's exact test was performed to determine the specificity of variants in these genes. Finally, SNVs and INDELs were identified by target enrichment sequencing. Gene ontology analysis of 112 genes with significant SNVs or INDELs in nonsmokers revealed that nonsynonymous SNVs in HECTD4 were significantly more frequent in nonsmokers than in smokers by target enrichment sequencing (p = .02). Further investigation of the function of HECTD4 variants as oncogenes in older nonsmokers is warranted.

LaSOM 335, active against bladder cancer cells, interferes with Let-60 (hRas) and reduces CD73 expression/activity.

Bladder cancer is the fourth most common malignancy in men. It can present along the entire continuum of severity, from mild to well-differentiated disease to extremely malignant tumors with low survival rates. Human RAS genes are the most frequently mutated oncogenes in human cancers, and the critical role of aberrant Ras protein function in carcinogenesis is well established. Therefore, considerable efforts have been devoted to the development of anti-Ras inhibitors for cancer treatment. This study presents the biphenyl dihydropyrimidinone LaSOM 335 with high activity against T24 bladder cancer cells (IC50 = 10.73 ± 0.53 μM) and selectivity of cytotoxicity for this cancer cell line compared to two non-cancer cell lines investigated. Furthermore, we also show that this compound reduced vulvar development in the mutant let-60 gene of Caenorhabditis elegans. Let-60 is a homolog of the mammalian Ras gene. In addition, we observed that LaSOM 335 inhibits the enzymatic activity of CD73 and decreases CD73 expression. Possibly, this expression decrease is due to downstream EGFR signaling via the Ras-Raf-ERK pathway, that directly regulates CD73 expression via ERK1/2. Evidence suggests that non-immunomodulating functions of CD73 play an equally important role for cancer cell survival, progression, and migration. Regarding we also notice that LaSOM 335 was safe in the in vivo model of C. elegans. The set of these findings makes this biphenyl dihydropyrimidinone a promising candidate for further investigations in the bladder cancer field.

Holothurin A Inhibits RUNX1-Enhanced EMT in Metastasis Prostate Cancer via the Akt/JNK and P38 MAPK Signaling Pathway.

Due to the challenge of prostate cancer (PCa) management, there has been a surge in efforts to identify more safe and effective compounds that can modulate the epithelial-mesenchymal transition (EMT) for driving metastasis. Holothurin A (HA), a triterpenoid saponin isolated from Holothuria scabra, has now been characterized for its diverse biological activities. However, the mechanisms of HA in EMT-driven metastasis of human PCa cell lines has not yet been investigated. Moreover, runt-related transcription factor 1 (RUNX1) acts as an oncogene in prostate cancer, but little is known about its role in the EMT. Thus, the purpose of this study was to determine how RUNX1 influences EMT-mediated metastasis, as well as the potential effect of HA on EMT-mediated metastasis in endogenous and exogenous RUNX1 expressions of PCa cell lines. The results demonstrated that RUNX1 overexpression could promote the EMT phenotype with increased EMT markers, consequently driving metastatic migration and invasion in PC3 cell line through the activation of Akt/MAPK signaling pathways. Intriguingly, HA treatment could antagonize the EMT program in endogenous and exogenous RUNX1-expressing PCa cell lines. A decreasing metastasis of both HA-treated cell lines was evidenced through a downregulation of MMP2 and MMP9 via the Akt/P38/JNK-MAPK signaling pathway. Overall, our approach first demonstrated that RUNX1 enhanced EMT-driven prostate cancer metastasis and that HA was capable of inhibiting the EMT and metastatic processes and should probably be considered as a candidate for metastasis PCa treatment.

YB-1 activating cascades as potential targets in KRAS-mutated tumors.

Y‑box binding protein‑1 (YB-1) is amultifunctional protein that is highly expressed in human solid tumors of various entities. Several cellular processes, e.g. cell cycle progression, cancer stemness and DNA damage signaling that are involved in the response to chemoradiotherapy (CRT) are tightly governed by YB‑1. KRAS gene with about 30% mutations in all cancers, is considered the most commonly mutated oncogene in human cancers. Accumulating evidence indicates that oncogenic KRAS mediates CRT resistance. AKT and p90 ribosomal S6 kinase are downstream of KRAS and are the major kinases that stimulate YB‑1 phosphorylation. Thus, there is aclose link between the KRAS mutation status and YB‑1 activity. In this review paper, we highlight the importance of the KRAS/YB‑1 cascade in the response of KRAS-mutated solid tumors to CRT. Likewise, the opportunities to interfere with this pathway to improve CRT outcome are discussed in light of the current literature.

Abstract B005: The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types

Abstract Background: ERG is the most common oncogene in prostate cancer, as it is aberrantly expressed in about 50% of cases due to the TMPRSS2/ERG gene rearrangement. ERG is not normally expressed in the adult prostate. The normal function of ERG is confined to hematopoietic stem cells and blood vessels. Aberrant expression of ERG in prostate epithelial cells is oncogenic when combined with mutations that activate the PI3K/AKT signaling pathway. The RAS/MAPK pathway can also regulate ERG function through direct phosphorylation of ERG by ERK. The function of these regulatory events and how they can be exploited to develop therapy for ERG-positive prostate cancer remains unclear. Results: ERG expression in prostate basal epithelial cells drives epithelial to mesenchymal transition and stemness properties. This function requires ERG phosphorylation via a positive feedback loop with the TLR4 signaling pathway, and can be repressed by a TLR4 inhibitor. Activation of the PI3K/AKT pathway rearranges the ERG cistrome and alters ERG function, where ERG now promotes luminal epithelial differentiation. In the presence of activated AKT, new ERG targets include genes involved in vascular development and ERG phosphorylation is regulated through a positive feedback loop with the VEGF signaling pathway. Conclusions: ERG function in basal and luminal prostate epithelial cells appear to mirror ERG functions in hematopoietic stem cells and blood vessels, respectively. These findings suggest strategies of combinatorial inhibition of ERG function in both cell types. Citation Format: Peter C. Hollenhorst, Saranya Rajendran, Travis J. Jerde. The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B005.

A phase II trial of JDQ443 in KRAS G12C-mutated NSCLC with PD-L1 expression &lt;1% or PD-L1 expression ≥1% and an STK11 co-mutation.

TPS9158 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). KRAS G12C, the most frequent KRAS variant, is found in ~13% of patients (pts) with NSCLC. KRAS is a GTPase that regulates cell signaling pathways necessary for proliferation, differentiation, and survival. KRAS mutation reduces the intrinsic GTPase activity of the enzyme, allowing for the accumulation of active, GTP-bound KRAS and hyperactivation of downstream signaling, driving tumorigenesis. JDQ443 is a potent, selective KRASG12C inhibitor that irreversibly traps KRASG12C in its inactive, GDP bound state and blocks downstream signaling. In preliminary data from the Phase Ib part of the KontRASt-01 study (NCT04699188), JDQ443 showed promising antitumor activity and an acceptable safety profile in previously treated pts with KRAS G12C-mutated advanced NSCLC. Pts with KRAS G12C-mutated NSCLC currently receive the same first-line (1L) treatment as those without driver mutations, consisting of immunotherapy alone or combined with chemotherapy; however, ~30% of pts with NSCLC present with programmed death-ligand 1 (PD-L1) expression &lt;1%, and ~10–20% of pts harbor an STK11 mutation, both indicators of poor response to immunotherapy. Therefore, alternative 1L treatment options are needed for these pts. Of note, PD-L1 expression and STK11 mutation do not affect responsiveness to KRASG12C inhibitors, raising interest in the evaluation of these targeted therapies as 1L alternatives to immunotherapy for pts with KRAS G12C-mutated NSCLC. Methods: KontRASt-06 (NCT05445843) is an open-label, Phase II, single-arm, multicenter study evaluating JDQ443 monotherapy (200 mg JDQ443 twice daily in 21-day cycles) as a 1L treatment for 2 cohorts of adult pts with locally advanced or metastatic, KRAS G12C-mutated NSCLC. Cohort A (n=90) includes pts whose tumors have PD-L1 expression &lt;1%, regardless of STK11 mutation status, while Cohort B (n=30) includes pts whose tumors have PD-L1 expression ≥1% and an STK11 co-mutation. Local testing for PD-L1 status and KRAS and STK11 mutations is accepted; KRAS and STK11 mutations may be assessed in blood samples. A tissue sample is required for retrospective biomarker status confirmation and exploratory study. The study is currently enrolling pts into both cohorts. The primary endpoint is the overall response rate (ORR) per RECIST version 1.1, assessed by a blinded independent review committee, in Cohort A. Key secondary endpoints are ORR in Cohort B and duration of response in both cohorts. Other secondary endpoints include progression-free survival, overall survival, safety, pharmacokinetics, and pt-reported outcomes. A comprehensive biomarker strategy aims to investigate predictors of treatment response and resistance in the study population. © 2023 American Association for Cancer Research®. Reused with permission. Clinical trial information: NCT05445843 .

Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers.

3151 Background: KRAS, a GTPase that regulates cellular growth, is the most frequently mutated oncogene in non-small cell lung, pancreatic and colorectal cancers. Hyperactivation of KRAS in mutant alleles result in upregulated signaling within the MAPK pathway leading to aberrant cell proliferation. In addition to the pan- and mutant-specific KRAS inhibitors, its upstream GEF activator, SOS1, has emerged as an attractive therapeutic target given its ability to regulate the active, GTP-loaded state of KRAS and mitigate MAPK pathway feedback. Methods: Utilizing our PRODEGY platform, we developed bifunctional CRBN-SOS1 degraders for the treatment of patients with KRAS-mutated cancers, independent of mutation type. Results: Our degraders display CRBN- and proteasome-mediated SOS1 degradation with DC50s &lt; 15nM in high-throughput (HiBiT) and traditional Western Blot assays in multiple mutant KRAS cell lines. SOS1 degradation resulted in the reduction of active KRAS, HRAS and MRAS levels when assayed by RAF-RBD pulldowns in MIA PaCa-2 (KRAS G12C) cells. Other downstream signaling markers (pERK and pS6) were also decreased upon SOS1 degradation in KRAS G12C, G12V, G12S and G13D cell lines in 3D Western Blot assays. Notably, the observed pERK and pS6 inhibition was driven by SOS1 degradation and not inhibition as decreases in signaling was no longer observed when SOS1 degraders were outcompeted with CRBN competitors. To assess the antiproliferative effects of our SOS1 degraders, we developed 3D proliferation assays in various KRAS mutant (G12A, G12C, G12D, G12V, G12S, G13C and G13D) as well as KRAS amplified cell lines and observed IC50s ranging from 0.5 - 70nM. Treatment of CRBN KO and SOS1 KO H358 and MIA PaCa-2 cell lines with our SOS1 degraders resulted in 100- to 400-fold IC50 values, validating that the functional activity observed is dependent on its targets. Consistent with our in vitro data, treatment of SOS1 degraders in MIA PaCa-2 xenografts resulted in &gt; 90% degradation and led to significant tumor growth inhibition. Given the diversity of mutations and tumors as well as acquired drug resistance to allele-specific KRAS inhibitors, we sought to determine if coupling SOS1 degradation with other EGFR-RAS-MAPK inhibitors could produce more potent responses to maximize patient benefit. Strong synergistic antiproliferative effects were observed when SOS1 degraders were co-treated with KRAS inhibitors AMG510 (G12C) and MRTX1133 (G12D) in respective KRAS-mutant cell lines as well as with MEK inhibition and EGFR inhibition. Lastly, combination of AMG510 or Trametinib with SOS1 degraders yielded strong synergy and a greater anti-tumor response in MIA PaCa-2 xenografts relative to the individual agents themselves. Conclusions: Together, these results highlight the potential of SOS1 degraders alone and in combination as therapeutic options for a variety of KRAS-driven cancers.

Circ_0079530 stimulates THBS2 to promote the malignant progression of non-small cell lung cancer by sponging miR-584-5p.

Circ_0079530 has been confirmed to be a novel potential oncogene in non-small cell lung cancer (NSCLC). This study aims to explore the role and mechanism of circ_0079530 in NSCLC progression. Levels of circ_0079530, microRNA (miR)-584-5p, thrombospondin-2 (THBS2), PCNA, Bax, E-cadherin, and ki67 were detected by quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. The proliferation of NSCLC cells was measured using cell counting kit 8 (CCK8) assay, colony formation assay, and EdU staining. Cell apoptosis and motility were respectively detected by flow cytometry and transwell assays. Interaction between miR-584-5p and circ_0079530 or THBS2 was predicted by bioinformatics analysis and confirmed via luciferase reporter assay and RNA immunoprecipitation (RIP) assay. A xenograft tumor model was used to analyze the role of circ_0079530 in tumor growth in vivo. Circ_0079530 was highly expressed in NSCLC tissues and cell lines. Circ_0079530 overexpression facilitated proliferation, migration, and invasion whereas it restrained the apoptosis of NSCLC cells. Circ_0079530 silence showed the opposite effects on the above malignant biological behaviors. Mechanistic analysis showed that circ_0079530 functioned as a sponge of miR-584-5p to relieve the suppressive action of miR-584-5p on its target THBS2. Additionally, circ_0079530 knockdown impeded the growth of xenografts in vivo. Circ_0079530 promoted NSCLC progression by regulating the miR-584-5p/THBS2 axis, providing a possible circRNA-targeted therapy for NSCLC.

Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.

e16297 Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]

KontRASt-02: A phase III trial investigating the efficacy and safety of the KRASG12C inhibitor JDQ443 vs docetaxel in patients with previously treated, locally advanced or metastatic, KRAS G12C-mutated NSCLC.

TPS9144 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) is the most frequent mutated oncogene in non-small cell lung cancer (NSCLC). KRAS G12C is the most common KRAS variant, present in ~13% of patients (pts) with non-squamous NSCLC. KRAS G12C mutations cause the accumulation of active, GTP-bound KRAS, which leads to activation of downstream pathways involved in cell proliferation and invasiveness. JDQ443 is a potent, structurally novel, selective KRASG12C inhibitor that irreversibly traps KRASG12C in its inactive, GDP-bound form. Data from the JDQ443 monotherapy arm of the first-in-human KontRASt-01 study demonstrated encouraging anti-tumor activity and an acceptable safety profile of JDQ443 in pts with previously treated, KRAS G12C-mutated, advanced NSCLC. For pts with advanced NSCLC who progress following first-line immunotherapy or doublet platinum-based chemotherapy, single agent docetaxel remains a standard option, although it presents modest activity and is generally poorly tolerated. In this context, alternative treatment options are needed to improve pt outcomes. Methods: KontRASt-02 (NCT05132075) is a global, Phase III, open-label, randomized, multicenter study evaluating JDQ443 as a monotherapy in comparison to docetaxel in pts with KRAS G12C-mutated, advanced NSCLC previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy (either in combination or as sequential treatments). Approximately 360 pts stratified by ECOG performance status (0 vs 1 and 2) and prior therapy (platinum-based chemotherapy and immunotherapy combined vs sequential) will be randomized at 1:1 to receive 200 mg oral JDQ443 twice daily continuously or 75 mg/m2 intravenous docetaxel once every 21 days. The primary endpoint of this study is progression-free survival (PFS) per Blinded Independent Review Committee (BIRC) according to RECIST version 1.1. The key secondary endpoint is overall survival (OS); other secondary endpoints include objective response rate, disease control rate, time to response, duration of response, PFS on subsequent therapy, safety of JDQ443 monotherapy, pt-reported outcomes, pharmacokinetics, time to deterioration of ECOG performance status, and safety in pts who crossover from docetaxel to JDQ443. Exploratory objectives include biomarker analyses aimed at investigating predictors of responsiveness to JDQ443. Pts randomized to docetaxel will be allowed to crossover to JDQ443 following confirmed disease progression per BIRC. To allow more pts to be treated with JDQ443, crossover will also be offered to all patients on docetaxel if the primary endpoint (PFS) is met. Treatment beyond progression will be allowed for pts receiving JDQ443 according to investigator judgement. The KontRASt-02 study is currently enrolling pts. Clinical trial information: NCT05132075 .

SNRPD1 inhibition suppresses the proliferation of hepatocellular carcinoma and promotes autophagy through the PI3K/AKT/mTOR/4EBP1 pathway

BackgroundSmall nuclear ribonucleoprotein Sm D1 (SNRPD1) has been reported as an oncogene in some solid cancers. Our previous study suggested that SNRPD1 has diagnostic and prognostic value in hepatocellular carcinoma (HCC), but its role in tumor growth and biological behavior remains unknown. In this study, we aimed to unravel the role and mechanism of SNRPD1 in HCC. MethodsWe investigated the SNRPD1 mRNA level in adjacent normal liver tissues and HCC tissues with different tumor stages in the UALCAN database. The associations between SNRPD1 mRNA expression and HCC prognosis were investigated in TCGA database. Then, 52 pairs of frozen HCC tissues and corresponding adjacent normal liver tissues were collected to perform qPCR and immunohistochemistry assay. Next, we carried out a series of experiments in vitro and in vivo to investigate the effects of SNRPD1 expression on cell invasion, migration, proliferation, autophagy, and the PI3K/AKT/mTOR pathway. ResultsThe bioinformatics analysis and qPCR in our patient cohort demonstrated that the SNRPD1 mRNA level in HCC tissues was higher than in adjacent normal tissues. In addition, the immunohistochemistry assay exhibited an increased SNRPD1 protein level with the tumor stage increase. Survival analysis suggested that higher expression of SNRPD1 was significantly associated with unfavorable prognosis of patients with HCC. The functional experiments in vitro indicated that SNRPD1 knockdown suppressed the cellular proliferation, migration, and invasion capacities. Furthermore, SNRPD1 inhibition induced cellular apoptosis and arrested the HCC cells at the G0/G1 phase of the cell cycle. Mechanistic analyses demonstrated that SNRPD1 knockdown induced the increase of autophagic vacuoles and the expression of autophagy-related genes (ATG5, ATG7, and ATG12) and blocked the PI3K/AKT/mTOR/4EBP1 pathway in vitro. Moreover, SNRPD1 inhibition suppressed tumor growth and expression of the Ki67 protein in vivo. ConclusionsSNRPD1 may serve as an oncogene in HCC and promote tumor proliferation via inhibiting autophagy induced through the PI3K/Akt/mTOR/4EBP1 pathway.

CDC23 knockdown suppresses the proliferation, migration and invasion of liver cancer via the EMT process.

Liver cancer (LC) is a malignant tumour that is associated with high mortality rates worldwide. Cell division cycle 23 (CDC23) acts as an oncogene in papillary thyroid cancer. In addition, epithelial-mesenchymal transition (EMT) is frequently involved in the malignant metastasis of various cancer types. Therefore, we hypothesized that CDC23 may regulate the malignant biological behaviours of LC cells through EMT. Proliferation, colony formation and Transwell assays, western blotting and xenograft experiments were performed. The results of the present study showed that CDC23 was highly expressed in LC cell lines. In addition, it was found via multiple in vitro assays that CDC23 knockdown reduced the proliferation, migration and invasion of LC cell lines. Finally, an in vivo study confirmed that CDC23 knockdown inhibited the growth of xenograft LC in nude mice. More importantly, the changes in the levels of EMT-related marker proteins were analysed in the sh-CDC23 group compared with the sh-NC group of cells and xenografts. E-cadherin was upregulated, and N-cadherin and vimentin were significantly downregulated after CDC23 silencing. Taken together, these results revealed that the knockdown of CDC23 inhibits the progression of LC by regulating EMT and that CDC23 may be a novel therapeutic target for LC.