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S100 calcium‐binding protein A (S100A) family members regulate multiple biological functions related to pancreatic cancer (PC) progression and metastasis. However, the prognostic and oncologic values of S100A family have not been systematically investigated in PC. In the present study, the mRNA expression and potential functions of S100A family were investigated by bioinformatic analysis. Our results demonstrated that overexpression of S100A2, S100A6, S100A10, S100A11, S100A14 and S100A16 was significantly associated with higher T stage, advanced histologic grade and worse prognosis in PC. Besides, one CpG of S100A2, three CpG of S100A6, four CpG of S100A10, four CpG of S100A11, two CpG of S100A14 and five CpG of S100A16 were negatively associated with corresponding S100A family members expression and positively associated with overall survival (OS). The signature based on four CpGs showed good prediction ability of OS. Besides, S100A2 overexpression took part in the regulation of mitotic cell cycle, ECM‐receptor interaction and HIF‐1α transcription factor network. Overexpression of S100A6, S100A10, S100A11, S100A14 and S100A16 may impair the infiltration and cytolytic activity of CD8+ T cells through focal adhesion‐Ras‐stimulating signalling pathway in PC. Overall, this study explores the multiple prognostic values and oncologic functions of the S100A family in PC.

Background To investigate whether common variants in EPHB4 and RASA1 are associated with cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. Methods Familial CCM cases enrolled in the Brain Vascular Malformation Consortium were included (n = 338). Total lesions and large lesions (≥5 mm) were counted on MRI; clinical history of ICH at enrollment was assessed by medical records. Samples were genotyped on the Affymetrix Axiom Genome‐Wide LAT1 Human Array. We tested the association of seven common variants (three in EPHB4 and four in RASA1) using multivariable logistic regression for ICH (odds ratio, OR) and multivariable linear regression for total and large lesion counts (proportional increase, PI), adjusting for age, sex, and three principal components. Significance was based on Bonferroni adjustment for multiple comparisons (0.05/7 variants = 0.007). Results EPHB4 variants were not significantly associated with CCM severity phenotypes. One RASA1 intronic variant (rs72783711 A>C) was significantly associated with ICH (OR = 1.82, 95% CI = 1.21–2.37, p = 0.004) and nominally associated with large lesion count (PI = 1.17, 95% CI = 1.03–1.32, p = 0.02). Conclusion A common RASA1 variant may be associated with ICH and large lesion count in familial CCM. EPHB4 variants were not associated with any of the three CCM severity phenotypes. We investigated whether common variants in EPHB4 and RASA1 are associated with familial cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. EPHB4 variants were not associated with any of the three CCM severity phenotypes. However, an intronic RASA1 variant was significantly associated with ICH and large lesion count in familial CCM, suggesting that the Ras‐Erk pathway may play a role in CCM disease severity.

The Kirsten rat sarcoma (KRAS) oncogene was considered “undruggable” until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib‐ and MRTX1133‐resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2‐mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS‐mutant pancreatic cancer. The authors found that administration of the KRAS inhibitors sotorasib or MRTX1133 to pancreatic cancer cell lines upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. Addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo.

The KRAS oncoprotein is a frequent tumor driver in lung, pancreatic, and colorectal cancers and has proven to be a challenging pharmaceutical target. The first KRAS‐targeted therapeutics are now being tested in clinical trials but the consequences of preferentially targeting the GDP or GTP state of KRAS and the relevance of RAS nanoclustering have remained unclear. Here we report a Designed Ankyrin Repeat Protein (DARPin) that recognizes the RAS switch I/II region with low nm affinity, independently of the nucleotide bound (GDP‐ or GTP state). This DARPin, termed ‘784_F5’, occupies the effector recognition lobe, resulting in interference with SOS‐mediated activation, RAS downstream effector interactions, and KRAS nanoclustering. Consequently, this anti‐RAS DARPin potently blocks downstream signaling, leading to a strong reduction in proliferation and anchorage‐independent growth in RAS‐dependent cell lines. We showed that the expression of ‘784_F5’, the pan‐RAS, nucleotide‐independent DARPin can lead to tumor regression in a colorectal xenograft model which may hold promise for further investigation and development. We report a Designed Ankyrin Repeat Protein that binds and inhibits RAS proteins, which serve as central cell signaling hubs and are essential for the progression of many cancers. Its unique feature is that it does not discriminate between different RAS isoforms or mutations and is capable of binding to RAS in both its active (GTP‐bound) and inactive (GDP‐bound) states.

The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.

Oncoprotein Y‐box‐binding protein‐1 (YB‐1) is involved in all cancer hallmarks. One of the most studied post‐translational modifications of YB‐1 is phosphorylation on Serine 102 (S102), which is involved in cancer progression. KRAS mutations are frequent, have been associated with poor prognosis and therapy resistance, and they are considered a major stimulator of S102 YB‐1 in vitro. In this study, a relationship between S102 YB‐1 phosphorylation in subcellular fractions and KRAS mutation was investigated in CRC tissues, and its association with clinicopathological parameters was analyzed. Immunohistochemistry on 36 patient samples and 5 normal tissue samples highlighted nuclear S102 YB‐1 was specific to cancer tissues. Nuclear S102 YB‐1 was expressed in 47.2% of tumor tissues, which was positively correlated with KRAS mutation (P = 0.017). There was no significant association between cytoplasmic S102 YB‐1 with KRAS mutation status (P = 0.391). Further studies in larger cohorts are needed to validate the observed results. The significant association between S102 YB‐1 in the nucleus and KRAS mutation may suggest YB‐1 as an effective target to improve survival of CRC patients with KRAS‐mutated tumors. This study identifies nuclear YB‐1 S102 phosphorylation as a marker associated with KRAS and FBXW7 mutations in colorectal cancer. Mutated KRAS correlates specifically with nuclear, not cytoplasmic, S102 YB‐1. These findings provide the first ex vivo evidence of this link in CRC and suggest future studies should assess the prognostic and therapeutic relevance of its subcellular localization.

Background Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biological roles of MAZ in bone metastasis of PCa remain unclear. Methods MAZ expression was examined in PCa tissues with bone metastasis, PCa tissues without bone metastasis and metastatic bone tissues by real-time PCR and immunohistochemistry (IHC), respectively. Statistical analysis was performed to evaluate the clinical correlation between MAZ expression and clinicopathological features and bone metastasis-free survival in PCa patients. Biological roles of MAZ in bone metastasis of PCa were investigated both in vitro by transwell assay, and in vivo by a mouse model of left cardiac ventricle inoculation. The bioinformatics analysis, western blot, pull-down assays, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were applied to demonstrate and examine the relationship between MAZ and its potential downstream signalling pathway. TaqMan copy number assay was performed to identify the underlying mechanism responsible for MAZ overexpression in PCa tissues. Results MAZ expression is elevated in PCa tissues with bone metastasis compared with that in PCa tissues without bone metastasis, and is further increased in metastatic bone tissues. High expression of MAZ positively correlates with poor overall and bone metastasis-free survival in PCa patients. Upregulating MAZ elevates, while silencing MAZ represses the invasion and migration abilities of PCa cells in vitro and bone metastasis ability in vivo. Our results further reveal that MAZ promotes bone metastasis of PCa dependent on KRas signalling, although MAZ transcriptionally upregulates KRas and HRas expression, where the Ral guanine nucleotide exchange factor (RalGEF) signaling is responsible for the different roles of KRas and HRas in mediating the pro-bone metastasis of MAZ in PCa. Finally, our results indicate that recurrent gains contribute to MAZ overexpression in a small portion of PCa tissues. Conclusion These results indicate that the MAZ/Kras/ RalGEF signalling axis plays a crucial role in promoting PCa cell bone metastasis, suggesting a potential therapeutic utility of MAZ in bone metastasis of PCa.

Summary Sclerotinia sclerotiorum causes white mold (also called stem rot, Sclerotinia blight, etc.) in many economically important plants. It is a notorious soilborne fungal pathogen due to its wide host range and ability to survive in soil for long periods of time as sclerotia. Although host‐induced gene silencing (HIGS) was recently demonstrated to be an effective method for controlling white mold, limited gene targets are available. Here, using a forward genetics approach, we identified a RAS‐GTPase activating protein, SsGAP1, which plays essential roles in sclerotia formation, compound appressoria production and virulence. In parallel, as revealed by our knockout analysis, the SsGAP1 ortholog in Botrytis cinerea, BcGAP1, plays similar roles in fungal development and virulence. By knocking down SsRAS1 and SsRAS2, we also revealed that both SsRAS1 and SsRAS2 are required for vegetative growth, sclerotia development, compound appressoria production and virulence in S. sclerotiorum. Due to the major roles these RAS signalling components play in Sclerotiniaceae biology, they can be used as HIGS targets to control diseases caused by both S. sclerotiorum and B. cinerea. Indeed, when we introduced HIGS constructs targeting SsGAP1, SsRAS1 and SsRAS2 in Nicotiana benthamiana and Arabidopsis thaliana, we observed reduced virulence. Taken together, our forward genetics gene discovery pipeline in S. sclerotiorum is highly effective in identifying novel HIGS targets to control S. sclerotiorum and B. cinerea.

The RAS signaling pathway, particularly through mutations in KRAS, NRAS, and HRAS, plays a pivotal role in driving oncogenesis in a wide range of cancers. For years, RAS proteins were deemed \"undruggable\" due to their smooth surface and lack of deep binding pockets. However, recent breakthroughs in targeting specific RAS mutations, particularly KRAS G12C , have revolutionized the field. The discovery of covalent inhibitors that bind to an allosteric pocket near the cysteine residue of KRAS G12C has led to the development of FDA-approved drugs, marking a significant milestone in RAS-targeted therapy. This review provides a comprehensive overview of the evolution of direct RAS inhibitors, focusing on the chemical development of small molecule inhibitors, molecular glues, protein degraders, and other emerging strategies. We highlight the structural evolution of KRAS inhibitors, from covalent fragment-based approaches to non-covalent inhibitors and pan-RAS targeting strategies. Additionally, we discuss the clinical progress of key inhibitors, including their efficacy, resistance mechanisms, and combination treatment options. Finally, this review explores other innovative approaches such as cyclopeptide inhibitors and outlines future directions of RAS-targeting strategies. The success of RAS-targeted therapies underscores the transformative potential of overcoming the \"undruggable\" nature of RAS, offering new hope for patients with RAS-driven cancers.

In addition to transmitting receptor‐mediated signals to adjust the gene expression profile of the cell, small GTPases of the Ras family also control the remodelling of the actin cytoskeleton. The conversion of Ras GTPases from their active to their inactive form is controlled by Ras GTPase‐activating proteins (RasGAPs). IqgC, a RasGAP from Dictyostelium discoideum, was originally assigned to the IQGAP family, but its sequence and recent functional analyses show that IqgC is more closely related to RasGAPs from the GAP1 family of fungi. IqgC has two prominent domains, a RasGAP domain and a C‐terminal RGCt domain, and interacts with Ras, Rab and Rap GTPases, but shows GTPase‐promoting activity only towards Ras. IqgC suppresses macroendocytosis but supports cell‐substratum adhesion and directed cell migration. Its localisation to macroendocytic cups is mediated by the RasGAP domain, whereas its localisation in ventral focal adhesions is mediated by the RGCt domain. We hypothesise that IqgC plays an important role in the balance between the competing feeding and migratory behaviour of amoeboid D. discoideum cells. IqgC is a RasGAP from Dictyostelium discoideum. IqgC binds RasG via its RasGAP domain and deactivates it on macroendocytic cups, thereby suppressing the uptake of fluid and particles. IqgC has a positive effect on cell‐substratum adhesion, and its RGCt domain is required for recruitment to ventral foci. IqgC also interacts with RapA, and both GTPases have a stimulatory effect on adhesion.