Dataset Information

Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.

ABSTRACT:

Background

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy.

Methods

Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDXs (patient-derived xenografts), we identified KRAS-mutated PDXs, from which primary cell lines were established. The different mutants were challenged with KRAS downstream inhibitors in in vitro and in vivo experiments.

Results

Cells expressing the rare KRAS A146T mutant showed lower RAS-GTP levels compared to those bearing the canonical G12/13D mutations. Nevertheless, all the KRAS-mutated cells displayed KRAS addiction. Surprisingly, even if the GEF SOS1 is considered critical for the activation of KRAS A146T mutants, its abrogation did not significantly affect cell viability. From the pharmacologic point of view, Trametinib monotherapy was more effective in A146T than in G12D-mutated models, suggesting a vulnerability to MEK inhibition. However, in the presence of mutations in the PI3K pathway, more frequently co-occurrent in A146T models, the association of Trametinib and the AKT inhibitor MK-2206 was required to optimize the response.

Conclusion

A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC.

SUBMITTER: Puliga E

PROVIDER: S-EPMC11016506 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.

Puliga Elisabetta E De Bellis Chiara C Vietti Michelina Sandra S Capeloa Tania T Migliore Cristina C Orrù Claudia C Baiocchi Gian Luca GL De Manzoni Giovanni G Pietrantonio Filippo F Reddavid Rossella R Fumagalli Romario Uberto U Ambrogio Chiara C Corso Simona S Giordano Silvia S

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20240123 3

<h4>Background</h4>Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy.<h4>Methods</h4>Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDX ...[more]

PMID: 38261067

Similar Datasets

Project description:Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity. The resulting non-native protein-protein interactions (PPIs) formed between the POI and E3 ligase lead to the formation of a stable ternary complex, enhancing cooperativity for TPD. A significant challenge in PROTAC design is the screening of the linkers to induce favorable non-native PPIs between POI and E3 ligase. Here, we present a physics-based computational protocol to predict noncanonical and metastable PPI interfaces between an E3 ligase and a given POI, aiding in the design of linkers to stabilize the ternary complex and enhance degradation. Specifically, we build the non-Markovian dynamic model using the Integrative Generalized Master equation (IGME) method from ∼1.5 ms all-atom molecular dynamics simulations of linker-less encounter complex, to systematically explore the inherent PPIs between the oncogene homologue protein and the von Hippel-Lindau E3 ligase. Our protocol revealed six metastable states each containing a different PPI interface. We selected three of these metastable states containing promising PPIs for linker design. Our selection criterion included thermodynamic and kinetic stabilities of PPIs and the accessibility between the solvent-exposed sites on the warheads and E3 ligand. One selected PPIs closely matches a recent cocrystal PPI interface structure induced by an experimentally designed PROTAC with potent degradation efficacy. We anticipate that our protocol has significant potential for widespread application in predicting metastable POI-ligase interfaces that can enable rational design of PROTACs.

Dataset Information

Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.

Background

Methods

Results

Conclusion

Publications

Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets