Design, synthesis, and evaluation of purine and pyrimidine-based KRAS G12D inhibitors: Towards potential anticancer therapy DOI Creative Commons
S.L. Park, Venu Venkatarame Gowda Saralamma, Sagar D. Nale

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(7), P. e28495 - e28495

Published: April 1, 2024

Oncogenic RAS mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective treatment. Current strategies to inhibit the KRAS G12D mutation have shown limited success, emphasizing urgent need new therapeutic approaches. In this study, we developed several novel compounds by designing synthesizing purine pyrimidine analogs as inhibitors mutation. Our synthesized demonstrated potent anticancer activity against cell lines with mutation, effectively impeding their growth. They also exhibited low toxicity normal cells, indicating selective action cells carrying Notably, lead compound, PU1-1, induced programmed death G12D-mutated reduced levels active its downstream signaling proteins. Moreover, PU1-1 significantly shrunk tumor size pancreatic xenograft model further validating potential agent. These findings highlight purine-based candidates targeted therapy. However, exploration optimization these are essential meet unmet clinical needs KRAS-mutant cancers.

Language: Английский

Targeting KRAS in pancreatic cancer DOI Open Access
Sandra Stickler,

Barbara H. Rath,

Gerhard Hamilton

et al.

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, Journal Year: 2024, Volume and Issue: 32(5), P. 799 - 805

Published: Jan. 1, 2024

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up 90% all pancreatic ductal adenocarcinomas (PDACs) constitutes an attractive target for therapy. However, the most common KRAS mutations PDAC are G12D (44%), G12V (34%) G12R (20%) that not amenable treatment by G12C-directed cysteine-reactive inhibitors such as Sotorasib Adagrasib exhibit clinical efficacy lung cancer. G12C mutant been treated with but this mutation detected only 2%-3% PDAC. Recently, G12D-directed MRTX1133 inhibitor entered trials more development. other may be targeted indirectly via inhibition cognate guanosine exchange factor (GEF) Son Sevenless 1 drives KRAS. These agents seem provide means frequent improve patient outcomes.

Language: Английский

Citations

18
Targeting KRAS: from metabolic regulation to cancer treatment DOI Creative Commons
Yanyan Shi, Huiling Zheng, Tianzhen Wang

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

Citations

4
The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy DOI Creative Commons

Qinglong Ma,

Wenyang Zhang, Kongming Wu

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Abstract KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis fatty acids nucleotides. However, beyond mechanisms KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related alterations cells explore prevalence significance mutation shaping tumor microenvironment influencing epigenetic modification via various molecular activities. Given rely these changes sustain cell growth survival, targeting processes may represent a promising therapeutic strategy for KRAS-driven cancers.

Language: Английский

Citations

4
A stumbling block in pancreatic cancer treatment: drug resistance signaling networks DOI Creative Commons
Jinming Liu, Biao Zhang,

Bingqian Huang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 13, 2025

The primary node molecules in the cell signaling network cancer tissues are maladjusted and mutated comparison to normal tissues, which promotes occurrence progression of cancer. Pancreatic (PC) is a highly fatal with increasing incidence low five-year survival rates. Currently, there several therapies that target networks PC. However, PC "cold tumor" unique immunosuppressive tumor microenvironment (poor effector T infiltration, antigen specificity), targeting single gene or pathway basically ineffective clinical practice. Targeted matrix therapy, targeted metabolic mutant vaccines, other emerging have shown great therapeutic potential, but results been disappointing. Therefore, we summarize identified potential drug-resistant aimed at overcoming barriers existing therapies.

Language: Английский

Citations

1
CASC8 activates the pentose phosphate pathway to inhibit disulfidptosis in pancreatic ductal adenocarcinoma though the c-Myc-GLUT1 axis DOI Creative Commons
Hong-Fei Yao,

Jieqiong Ge,

Jiahao Chen

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 27, 2025

Abstract Purpose Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm existence disulfidptosis pancreatic ductal adenocarcinoma (PDAC) elucidate role Cancer Susceptibility 8 (CASC8) this process. Methods The PDAC was assessed using flow cytometry staining. CASC8 its clinical correlations were analyzed data from Genome Atlas (TCGA) further verified by chromogenic situ hybridization assay tissues. Cells knockdown overexpression subjected cell viability, EdU, transwell assays, used establish subcutaneous orthotopic tumor models. Disulfidptosis detected immunofluorescence assays. RNA sequencing metabolomics analysis performed determine metabolic pathways which significantly affected after knockdown. We glucose consumption NADP + /NADPH ratio investigate alterations profiles. immunoprecipitation combined fluorescence identify protein-RNA interactions. Protein stability, western blotting quantitative real-time PCR assays reveal potential molecular mechanism. Results observed could be rescued inhibitors. higher samples compared normal tissue. High correlated poor prognosis for patients contributed cancer progression vitro vivo. Furthermore, associated resistance under conditions PDAC. Mechanistically, interacted c-Myc enhance stability protein, leading activation pentose phosphate pathway, reduction ultimately inhibiting conditions. Conclusions provides evidence reveals upregulation malignancy. we demonstrate that acts as crucial regulator pathway disulfidptosis, thereby promoting progression.

Language: Английский

Citations

1
Deciphering cellular plasticity in pancreatic cancer for effective treatments DOI
Md. Hafiz Uddin,

Zhang Ding-qiang,

Irfana Muqbil

et al.

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 43(1), P. 393 - 408

Published: Jan. 9, 2024

Language: Английский

Citations

4
Advances of immune-checkpoint inhibition of CTLA-4 in pancreatic cancer DOI Open Access
Ran Ni, Zhiming Hu, Ran Tao

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117430 - 117430

Published: Sept. 10, 2024

Language: Английский

Citations

4
Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets DOI Creative Commons
Yutong Zhao,

C.M. Qin,

Lin Chen

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(6), P. 189183 - 189183

Published: Sept. 19, 2024

Language: Английский

Citations

4
Advances in Novel Targeted Therapies for Pancreatic Adenocarcinoma DOI Creative Commons
Tuan Hoang, Erica S. Tsang

Journal of Gastrointestinal Cancer, Journal Year: 2025, Volume and Issue: 56(1)

Published: Jan. 6, 2025

Language: Английский

Citations

0
FOXM1-Driven CKS1B Upregulation Promotes Pancreatic Cancer Progression and Therapeutic Resistance DOI Creative Commons
Li Zhang, Fang Wei,

Qihui Sun

et al.

International Journal of Biological Sciences, Journal Year: 2025, Volume and Issue: 21(3), P. 1047 - 1064

Published: Jan. 13, 2025

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited treatment options. Investigating novel therapeutic targets and understanding mechanisms of chemoresistance are crucial for improving patient outcomes. This study investigated the role CKS1B in PDAC carcinogenesis, stemness chemoresistance, explores underlying driving its upregulation. The findings may provide insights potential strategies PDAC. Methods: expression was analyzed tissues cell lines, impact on proliferation, migration, apoptosis, chemosensitivity were evaluated by using vitro vivo models, mechanistic connection to transcription factor FOXM1 explored molecular biology methods. Results: significantly upregulated correlated poor survival. promoted inhibited apoptosis. Expression enhanced properties pancreatic cancer. knockdown sensitized cells gemcitabine oxaliplatin. Mechanistically, is transcriptionally regulated FOXM1, establishing FOXM1-CKS1B signaling axis that regulates stemness, drug resistance Conclusions: Our strongly suggest plays critical progression, chemoresistance. Targeting represents promising strategy patients.

Language: Английский

Citations

0