KRAS V12

We established an HBEC3 cell line, designated as HBEC3-BIN, that expresses mutant BRAFV600E in a doxycycline-regulated manner...This contrast may result from differences in activation signaling in the downstream pathways. Furthermore, HBEC3 cells appear to be inherently resistant to OIS, which may be partly due to the fact that p21 remains localized in the cytoplasm upon expression of BRAFV600E or KRASV12.

Western blot analyses revealed pronounced reduction of E-cadherin and NCAM in the Akt3-kd cells, whereas Akt1 and Akt2 depletion upregulated E-cadherin, especially in H23 lung carcinoma cells. In summary, we identified oncogenic K-Ras4B as a key regulator of PI3-Kα-Akt signaling and Akt3 as a crucial regulator of K-Ras4B-induced modulation of E-cadherin and NCAM expression and localization.

MDC-MMAE was pre-clinically evaluated both in-vitro and in-vivo, in human MM cell lines, patient cells and a doxycycline inducible mutant KRAS cell system...It can also be combined with other MM standard of care drugs and with immunotherapy drugs to have a potentially important clinical effect. In collaboration with Tezcat Biosciences, the MDC-MMAE technology has achieved a phase II SBIR for advancement to clinical application.

Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.

This study details the most prevalent KRAS alterations and co-mutations among KRASalt NSCLC. KRAS p.G12C was the most frequently observed alteration and co-mutations were found in TP53, LRP1B, STK11, KEAP1, and CDKN2A. Our findings have therapeutic implications as co-alterations with STK11/KEAP1 are associated with worse outcomes.

We demonstrated a synergistic combination between ADGN-121/Abraxane in pancreatic carcinoma and between ADGN-122/Capecitabine in colon Adenocarcinoma. We showed, that ADGN-123 containing gRNAG12C can effectively reduce the proliferation and inhibit ERK phosphorylation of sotorasib/adagrasib acquired resistance cells harboring KRASG12C/R68M and KRASG12C/Y96D mutations...ConclusionOur study provides a proof-of-concept that ADGN can be applied to target driver mutations of cancers in vivo and permanently disrupt the oncogenic alleles, leading to major tumor regression. ADGN-123 constitutes an alternative strategy to overcome resistance associated to inhibitors of KRASG12C.

In this study, the hepatocellular promoting effect of MC-LR was described in Kras transgenic zebrafish, a doxycycline (DOX) inducible HCC model...Furthermore, the mRNA expression and protein abundance of β-Catenin in Wnt signaling pathway were significantly up-regulated following exposure to MC-LR. In short, our results suggested that MC-LR significantly inhibited the activity of PP2A, which in turn activated Wnt signaling, eventually resulting in progression of liver tumor in transgenic zebrafish.

Experiments using HIF-1α inhibitor or CXCR4 silencing with EVs administration clearly showed the role of hypoxia-induced CXCR4 pathway in the modulation of CD133 phenotype. Conclusion Our findings demonstrated that EVs from COPD patients are able to expand the CSC subsets in non-tumorigenic epithelial cells towards pro-tumorigenic/metastatic phenotype.

Overall, this novel work demonstrates that EC expression of k-RasV12 disrupts capillary assembly due to markedly excessive lumen formation coupled with strongly reduced pericyte recruitment and basement membrane deposition, which are critical pathogenic features predisposing the vasculature to develop arteriovenous malformations.

17 TP53 p.R249S 18 TP53 p.R158H 19 TP53 p.S215R 20 TP53 p.P278L 21 TP53 p.R283H 22 TP53 p.P278S; TP53 p.G279E; TP53 c.375+3_375+4insG; p.? 23 TP53 p.R267Q 24 TP53 p.C238F; TP53 p.C275S 25 TP53 p.Y163C 26 TP53 p.R248W 27 TP53 p.S241F 28 TP53 p.V272G Conclusion For patients in whom molecular analysis on tissue cannot be performed, NGS analysis of cfDNA in plasma provides an opportunity to detect driver mutations for subsequent targeted therapy.

In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.