A H-REV107 Peptide Inhibits Tumor Growth and Interacts Directly with Oncogenic KRAS Mutants

Kirsten-RAS (KRAS) has been the target of drugs because it is the most mutated gene in human cancers. Because of the low affinity of drugs for KRAS mutations, it was difficult to target these tumor genes directly. We found a direct interaction between KRAS G12V and tumor suppressor novel H-REV107 peptide with high binding affinity. We report the first crystal structure of an oncogenic mutant, KRAS G12V-H-REV107. This peptide was shown to interact with KRAS G12V in the guanosine diphosphate (GDP)-bound inactive state and to form a stable complex, blocking the activation function of KRAS. We showed that the peptide acted as an inhibitor of mutant KRAS targets by [α-32P] guanosine triphosphate (GTP) binding assay. The H-REV107 peptide inhibited pancreatic cancer and colon cancer cell lines in cell proliferation assay. Specially, the H-REV107 peptide can suppress pancreatic tumor growth by reduction of tumor volume and weight in xenotransplantation mouse models. Overall, the results presented herein will facilitate development of novel drugs for inhibition of KRAS mutations in cancer patients.

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Role of Protein kinase D2 in pancreatic tumor growth and tumor angiogenesis

Zeitschrift für Gastroenterologie ◽

10.1055/s-0030-1263395 ◽

2010 ◽

Vol 48 (08) ◽

Author(s):

N Azoitei ◽

GV Pusapati ◽

A Kleger ◽

C Brunner ◽

F Genze ◽

...

Keyword(s):

Protein Kinase ◽

Tumor Growth ◽

Tumor Angiogenesis ◽

Pancreatic Tumor

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The Inhibition Effect of Caveolin-1 on PANC1 Human Pancreatic Tumor Growth In vitro and In vivo*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2011.00168 ◽

2012 ◽

Vol 38 (12) ◽

pp. 1121-1131

Author(s):

Xiao-Hui WANG ◽

Ya-Min ZHENG ◽

Ye-Qing CUI ◽

Shuang LIU ◽

Hai-Chen SUN ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Tumor ◽

Caveolin 1 ◽

Inhibition Effect

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Blocking gp130-mediated IL-6 and Oncostatin M signaling inhibits pancreatic tumor growth in vivo

10.1055/s-0041-1733569 ◽

2021 ◽

Author(s):

I Pozios ◽

E Günzler ◽

N Hering ◽

M Arndt ◽

C Kamphues ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Tumor ◽

Oncostatin M

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Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a

Molecular Pharmacology ◽

10.1124/mol.110.064451 ◽

2010 ◽

Vol 78 (2) ◽

pp. 226-236 ◽

Cited By ~ 68

Author(s):

Indira Jutooru ◽

Gayathri Chadalapaka ◽

Maen Abdelrahim ◽

Md Riyaz Basha ◽

Ismael Samudio ◽

...

Keyword(s):

Transcription Factors ◽

Tumor Growth ◽

Pancreatic Tumor ◽

Specificity Protein ◽

Protein Transcription

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Rapid Estrogen-Induced Phosphorylation of the SRC-3 Coactivator Occurs in an Extranuclear Complex Containing Estrogen Receptor

Molecular and Cellular Biology ◽

10.1128/mcb.25.18.8273-8284.2005 ◽

2005 ◽

Vol 25 (18) ◽

pp. 8273-8284 ◽

Cited By ~ 54

Author(s):

Fuzhong F. Zheng ◽

Ray-Chang Wu ◽

Carolyn L. Smith ◽

Bert W. O'Malley

Keyword(s):

Estrogen Receptor ◽

Ligand Binding ◽

Direct Interaction ◽

Activation Function ◽

Estrogen Receptor Α ◽

Binding Domain ◽

Phosphorylation Sites ◽

Binding Domains ◽

Nongenomic Action ◽

Binding Groove

ABSTRACT SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 is a primary transcriptional coregulator for estrogen receptor (ER). Six SRC-3 phosphorylation sites have been identified, and these can be induced by steroids, cytokines, and growth factors, involving multiple kinase signaling pathways. Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor α (ERα) or activated ERβ is present. Both the activation function 1 and the ligand binding domains of ERα are required for maximal induction. Mutations in the coactivator binding groove of the ERα ligand binding domain inhibit E2-stimulated SRC-3 phosphorylation, as do mutations in the nuclear receptor-interacting domain of SRC-3, suggesting that ERα must directly contact SRC-3 for this posttranslational modification to take place. A transcriptionally inactive ERα mutant which localizes to the cytoplasm supports E2-induced SRC-3 phosphorylation. Mutations of the ERα DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation. Together these data demonstrate that E2-induced SRC-3 phosphorylation is dependent on a direct interaction between SRC-3 and ERα and can occur outside of the nucleus. Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators.

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MetMAb, the One-Armed 5D5 Anti-c-Met Antibody, Inhibits Orthotopic Pancreatic Tumor Growth and Improves Survival

Cancer Research ◽

10.1158/0008-5472.can-07-5960 ◽

2008 ◽

Vol 68 (11) ◽

pp. 4360-4368 ◽

Cited By ~ 166

Author(s):

Hongkui Jin ◽

Renhui Yang ◽

Zhong Zheng ◽

Mally Romero ◽

Jed Ross ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Tumor ◽

The One

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Cholecystokinin-Receptor Antagonists in Experimental Pancreatic Tumor Growth

Cholecystokinin Antagonists in Gastroenterology ◽

10.1007/978-3-642-76362-5_22 ◽

1991 ◽

pp. 203-208 ◽

Cited By ~ 3

Author(s):

C. B. H. Lamers ◽

B. R. Douglas ◽

J. B. M. Jansen ◽

R. A. Woutersen

Keyword(s):

Tumor Growth ◽

Pancreatic Tumor ◽

Receptor Antagonists ◽

Cholecystokinin Receptor

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A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses

npj Vaccines ◽

10.1038/s41541-020-00253-9 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Carlos A. Arbelaez ◽

Juan Estrada ◽

Melissa A. Gessner ◽

Charles Glaus ◽

Agnieszka B. Morales ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Tumor Antigens ◽

T Cell Responses ◽

Tumor Growth Inhibition ◽

Lymphoid Tissues ◽

Dependent Manner ◽

Kras Mutations ◽

Peptide Antigens ◽

Cell Responses

AbstractCancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but the outcomes have been unimpressive, perhaps because these peptides elicit predominantly CD4+ T cell responses. We hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improved anti-tumor responses. Here, we have designed SLP-containing cationic lipoplexes (SLP–Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using the G12D KRAS mutations as neoantigens, we found that vaccination of mice with naked synthetic peptides harboring the G12D mutation with CpG adjuvant stimulated mainly CD4+ T cell responses with limited tumor growth inhibition. On the other hand, immunization with SLP–Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combination of the SLP–Lpx vaccines with a checkpoint inhibitor led to profound growth suppression of established tumors. These studies suggest that preferential targeting of peptides derived from neoantigens to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.

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