Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA994125 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25249045.fastq.gz | Fastqsanger.gz | |||
| SRR25249046.fastq.gz | Fastqsanger.gz | |||
| SRR25249047.fastq.gz | Fastqsanger.gz | |||
| SRR25249048.fastq.gz | Fastqsanger.gz | |||
| SRR25249049.fastq.gz | Fastqsanger.gz |
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Project description:Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.
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Project description:Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to Sustained MAPK-Targeted Therapy in KRAS-Mutant Cancers
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Project description:Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS, for example, is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to second-generation MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to sustained MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.
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Project description:Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.
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Project description:Mutational activation of the KRAS oncogene is a major genetic driver of pancreatic ductal adenocarcinoma (PDAC) growth. KRAS-dependent PDAC growth is mediated primarily through persistent activation of the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade, one of the most extensively studied cancer signaling networks. While substrates of RAF and MEK kinases are highly restricted, ERK1/2 has been attributed to over 1,000 substrates. In this study, we used the highly selective ERK1/2 inhibitor, SCH772984, and proteomic and phosphoproteomic analyses to extend the repertoire of ERK-dependent phosphosites and phosphoproteins in PDAC. We validated the specificity of SCH772984 in our cell lines using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). We then performed phosphoproteomics and global proteomics in a panel of PDAC cell lines and identified 5,117 ERK-dependent phosphosites on 2,252 proteins, of which 88% and 67%, respectively, were not previously associated with ERK. We then utilized our recently annotated serine/threonine kinome motif database to dissect the phosphoproteome and reveal an expansive ERK-regulated kinase network. We found that ERK- and immediate downstream kinase RSK-substrate motifs predominated after one hour of ERK inhibition, whereas cell cycle regulatory cyclin-dependent kinase motifs predominated by 24 h, reflecting a highly dynamic ERK-dependent phosphoproteome. We find compensatory activation of HIPK, CLK, PKN, PAK, and DYRK family kinases. Finally, using the genome-wide CRISPR-Cas9 dataset in the Cancer Dependency Map portal (DepMap), we determined that approximately 18% of ERK dependent phosphoproteins are essential for pancreatic cancer growth, and these are enriched in nuclear proteins. Together, our findings provide a system-wide profile of the mechanistic basis for ERK-driven pancreatic cancer growth.
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