Site-specific mutagenesis screening in KRAS mutant library to uncover resistance mechanisms to KRASG12D inhibitors DOI
Jeesoo Choi, J. H. Shin,

Taeyul K. Kim

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 591, P. 216904 - 216904

Published: April 18, 2024

Language: Английский

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver DOI Open Access
Javier Ros, Caterina Vaghi, Iosune Baraibar

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3304 - 3304

Published: March 14, 2024

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated in human cancer. In colorectal cancer (CRC), KRAS mutations are present more than 50% of cases, and glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs up to 4% patients. This associated with short responses standard chemotherapy worse overall survival compared non-G12C mutations. recent years, several G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification negative feedback through EGFR receptor has led development plus an anti-EGFR combination, thus boosting antitumor activity. Currently, under development, results from phase I II trials promising. Moreover, III CodeBreaK 300 trial demonstrates superiority sotorasib-panitumumab over trifluridine/tipiracil, establishing a new care for harboring Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib also shown meaningful response rate currently evaluation. Nonetheless, these will relapse. this setting, liquid biopsy emerges critical tool characterize mechanisms resistance, consisting mainly acquired genomic alterations MAPK PI3K pathways tyrosine kinase alterations, but gene fusions, histological changes, conformational changes been described. paper, we review well main resistance.

Language: Английский

Citations

15
Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets DOI
Edward W. Tate, Lior Soday,

Ana Losada de la Lastra

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(4), P. 240 - 260

Published: Feb. 29, 2024

Language: Английский

Citations

14
Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer DOI
Caicun Zhou,

Chongyang Li,

Libo Luo

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(7), P. 1286 - 1300.e8

Published: June 27, 2024

Language: Английский

Citations

12
MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer DOI Creative Commons
Sílvia Casacuberta‐Serra, Íñigo González-Larreategui,

Daniel Capitán-Leo

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 21, 2024

Abstract RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with being frequently mutated amplified. The cooperative interplay between constitutes a complex multifaceted phenomenon, profoundly influencing tumor development. Together individually, these two regulate most, if not all, hallmarks of including cell death escape, replicative immortality, tumor-associated angiogenesis, invasion metastasis, metabolic adaptation, immune evasion. Due to their frequent alteration role tumorigenesis, emerge as highly appealing targets cancer therapy. However, due nature, both have been long considered “undruggable” and, until recently, no drugs directly targeting them had reached clinic. This review aims shed light on partnership, special attention active collaboration fostering an immunosuppressive milieu driving immunotherapeutic resistance cancer. Within this review, we also present update different inhibitors currently undergoing clinical trials, along outcomes combination strategies explored overcome drug resistance. recent development suggests paradigm shift long-standing belief “undruggability”, hinting at new era therapeutic targeting.

Language: Английский

Citations

11
KRAS inhibitors: resistance drivers and combinatorial strategies DOI Creative Commons
Tamara Isermann, Christine Sers, Channing J. Der

et al.

Trends in cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

Citations

11
RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms DOI Creative Commons

Xiaojuan Yang,

Hong Wu

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Nov. 9, 2024

Variants in the RAS family (HRAS, NRAS and KRAS) are among most common mutations found cancer. About 19% patients with cancer harbor mutations, which typically associated poor clinical outcomes. Over past four decades, KRAS has long been considered an undruggable target due to absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements drug design have made RAS-targeting therapies viable, particularly approval direct

Language: Английский

Citations

6
Structural Insights into Small-Molecule KRAS Inhibitors for Targeting KRAS Mutant Cancers DOI
Divya Pandey,

Subhash C. Chauhan,

Vivek K. Kashyap

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116771 - 116771

Published: Aug. 15, 2024

Language: Английский

Citations

5
Novel RAF‐directed approaches to overcome current clinical limits and block the RAS/RAF node DOI Creative Commons
Rossella Scardaci, Ewa Berlinska,

Pietro Scaparone

et al.

Molecular Oncology, Journal Year: 2024, Volume and Issue: 18(6), P. 1355 - 1377

Published: Feb. 16, 2024

Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations cancer and RASopathies, while RAS oncogene activation alone affects 19% of all patients accounts for approximately 3.4 million new cases every year, less cascade's downstream effectors also involved etiology. proteins initiate signaling cascade by promoting dimerization RAF kinases, which can act as oncoproteins well: BRAF V600E is most common oncogenic driver, mutated 8% malignancies. Research this field led to development drugs that target BRAFV600‐like mutations (Class I), now utilized clinics, but cause paradoxical resistance development. Furthermore, they ineffective against non‐BRAFV600E malignancies dimerize could be either RTK/RAS independent or dependent II III, respectively), still lacking an effective treatment. This review discusses recent advances anti‐RAF therapies, including paradox breakers, dimer‐inhibitors, immunotherapies, other novel approaches, critically evaluating their efficacy overcoming therapeutic limitations, putative role blocking pathway.

Language: Английский

Citations

4
The kinase domain of TRPM7 interacts with PAK1 and regulates pancreatic cancer cell epithelial-to-mesenchymal transition DOI Creative Commons
Mathieu Gautier, Julie Auwercx, Bernadette Neve

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the main and deadliest form of pancreatic cancer. This a major problem public health since it will become second leading cause death by cancer in next few years, mainly due to lack efficient therapies. Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) protein, cation channel fused with serine/threonine kinase domain overexpressed PDAC associated low survival. In this work, we aim study role on cell fates using model deletion CRISPR-Cas9. PANC-1 MIA PaCa-2 lines were used was deleted CRISPR-Cas9 strategy. Kinase (ΔK) validated RT-qPCR western-blots. The effect function studied patch-clamp Mn2+-quenching. phenotype MTT migration/invasion assays. Finally, in vivo xenografted mice. Here show that TRPM7 required maintain mesenchymal cells. We also demonstrated PAK1 interact same protein complexes. Moreover, for carcinogenesis dissemination vivo. Intriguingly, specific may depend KRAS oncogene mutation status. conclusion, aggressive cells, could be promising target against PDAC.

Language: Английский

Citations

0
Characterization of A Bronchoscopically Induced Transgenic Lung Cancer Pig Model for Human Translatability DOI Creative Commons
Jussuf T. Kaifi, Kirtan Joshi, Kanve N. Suvilesh

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract Background There remains a need for animal models with human translatability in lung cancer (LC) research. Findings pigs have high impact on humans due to similar anatomy and physiology. We present the characterization of bronchoscopically-induced LC model Oncopigs carrying inducible KRASG12D TP53R167H mutations. Methods Twelve underwent 29 injections via flexible bronchoscopy. Eighteen Adenovirus-Cre recombinase gene (AdCre) inductions were performed endobronchially (n = 6) transbronchially needle 12). Eleven control without AdCre. serial contrast-enhanced chest CT clinical follow-up weeks. Following autopsy, organ tissues histopathology, immunohistochemistry, RNA-sequencing comparative analysis The Cancer Genome Atlas (TCGA) data. Results All 18 sites AdCre had consolidations imaging. Transbronchial led histopathologic invasive and/or carcinoma situ (CIS) 11/12 (91.7%), (excluding CIS) 8/12 (66.6%). Endobronchial 3/6 (50%). A soft tissue metastasis was observed one Oncopig. Immunohistochemistry confirmed expression Pan-CK+/epithelial cells, macrophages T cells infiltration tumor microenvironment. Transcriptome comparison showed 54.3% overlap (TCGA), contrast 29.88% KRAS-mutant mouse LC. Conclusions transgenic immunocompetent Oncopig has rate following bronchoscopic transbronchial induction. Overlap transcriptome noted. This pig is expected patient.

Language: Английский

Citations

0