ARID1A-induced transcriptional reprogramming rewires signalling responses to drug treatment in melanoma DOI Creative Commons
Charlie George Barker, Sumana Sharma, Ana Mafalda Santos

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Abstract Resistance to BRAF and MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive acquired mechanisms that allow tumour cells evade therapy. Here, we examined early signalling responses single combined inhibition BRAFV600E, drug-sensitive cell line drug-resistant ARID1A-knockout (KO) derivative. ARID1A, frequently mutated melanoma, associated with resistance immune evasion. Using an innovative systems biology approach integrates transcriptomics, proteomics, phosphoproteomics, functional kinomics through matrix factorization network analysis, identified key alterations mechanisms. We found ARID1A-KO exhibited transcriptional rewiring, sustaining MAPK1/3 JNK activity post-treatment, bypassing feedback sensitivity observed parental cells. This rewiring suppressed PRKD1 activation, increased JUN activity—a central node—and disrupted PKC dynamics elevated basal RTKs (e.g., EGFR, ROS1) Ephrin receptor post-treatment. ARID1A mutations also reduced HLA-related protein expression enriched extracellular components, potentially limiting infiltration reducing immunotherapy efficacy. Our graph-theoretical multi-omics uncovered novel resistance-associated pathways, identifying PRKD1, JUN, NCK1 as critical nodes. While activation redundancies complicate single-target therapies, they present opportunities for combination strategies. study highlights ARID1A’s role reshaping interactions, offering new insights into By actionable targets, including provide foundation developing integrated therapeutic strategies overcome BRAF/MAPK inhibitor-treated melanoma. One sentence summary reveals how ARID1A-mediated drives altering dynamics, highlighting potential targets combinatorial therapies.

Язык: Английский

ARID1A-Induced Transcriptional Reprogramming Rewires Signalling Responses to Drug Treatment in Melanoma DOI Creative Commons
Charlie George Barker, Sumana Sharma, Ana Mafalda Santos

и другие.

Опубликована: Янв. 7, 2025

Resistance to BRAF and MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive acquired mechanisms that allow tumour cells evade therapy. Here, we examined early signalling responses single combined inhibition BRAFV600E, drug-sensitive cell line drug-resistant ARID1A-knockout (KO) derivative. ARID1A, frequently mutated melanoma, associated with resistance immune evasion. Using an innovative systems biology approach integrates transcriptomics, proteomics, phosphoproteomics, functional kinomics through matrix factorization network analysis, identified key alterations mechanisms. We found ARID1A-KO exhibited transcriptional rewiring, sustaining MAPK1/3 JNK activity post-treatment, bypassing feedback sensitivity observed parental cells. This rewiring suppressed PRKD1 activation, increased JUN activity—a central node—and disrupted PKC dynamics elevated basal RTKs (e.g., EGFR, ROS1) Ephrin receptor post-treatment. ARID1A mutations also reduced HLA-related protein expression enriched extracellular components, potentially limiting infiltration reducing immunotherapy efficacy. Our graph-theoretical multi-omics uncovered novel resistance-associated pathways, identifying PRKD1, JUN, NCK1 as critical nodes. While activation redundancies complicate single-target therapies, they present opportunities for combination strategies. study highlights ARID1A’s role reshaping interactions, offering new insights into By actionable targets, including provide foundation developing integrated therapeutic strategies overcome BRAF/MAPK inhibitor-treated melanoma. ONE SENTENCE SUMMARY: reveals how ARID1A-mediated drives altering dynamics, highlighting potential targets combinatorial therapies.

Язык: Английский

Процитировано

0
NetworkCommons: bridging data, knowledge and methods to build and evaluate context-specific biological networks DOI Creative Commons
Víctor Patón, Dénes Türei, Olga Ivanova

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 25, 2024

Abstract Summary We present NetworkCommons, a platform for integrating prior knowledge, omics data, and network inference methods, facilitating their usage evaluation. NetworkCommons aims to be an infrastructure the biology community that supports development of better methods benchmarks, by enhancing interoperability integration. Availability Implementation is implemented in Python offers programmatic access multiple datasets, benchmarking setups. It free software, available at https://github.com/saezlab/networkcommons . Contact [email protected] , [email protected] Supplementary Data Contribution guidelines, additional figures, descriptions evaluation strategies implementation are documentation https://networkcommons.readthedocs.io/

Язык: Английский

Процитировано

0
ARID1A-induced transcriptional reprogramming rewires signalling responses to drug treatment in melanoma DOI Creative Commons
Charlie George Barker, Sumana Sharma, Ana Mafalda Santos

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Abstract Resistance to BRAF and MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive acquired mechanisms that allow tumour cells evade therapy. Here, we examined early signalling responses single combined inhibition BRAFV600E, drug-sensitive cell line drug-resistant ARID1A-knockout (KO) derivative. ARID1A, frequently mutated melanoma, associated with resistance immune evasion. Using an innovative systems biology approach integrates transcriptomics, proteomics, phosphoproteomics, functional kinomics through matrix factorization network analysis, identified key alterations mechanisms. We found ARID1A-KO exhibited transcriptional rewiring, sustaining MAPK1/3 JNK activity post-treatment, bypassing feedback sensitivity observed parental cells. This rewiring suppressed PRKD1 activation, increased JUN activity—a central node—and disrupted PKC dynamics elevated basal RTKs (e.g., EGFR, ROS1) Ephrin receptor post-treatment. ARID1A mutations also reduced HLA-related protein expression enriched extracellular components, potentially limiting infiltration reducing immunotherapy efficacy. Our graph-theoretical multi-omics uncovered novel resistance-associated pathways, identifying PRKD1, JUN, NCK1 as critical nodes. While activation redundancies complicate single-target therapies, they present opportunities for combination strategies. study highlights ARID1A’s role reshaping interactions, offering new insights into By actionable targets, including provide foundation developing integrated therapeutic strategies overcome BRAF/MAPK inhibitor-treated melanoma. One sentence summary reveals how ARID1A-mediated drives altering dynamics, highlighting potential targets combinatorial therapies.

Язык: Английский

Процитировано

0