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| Status |
Public on May 15, 2024 |
| Title |
Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
RNA extracted from cell lines treated in each indicated condition were treated with RNA-sequencing. All experiments were performed in biological triplicate.
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| Contributor(s) |
Nussbaum D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jul 12, 2023 |
| Last update date |
May 15, 2024 |
| Contact name |
Daniel Philip Nussbaum |
| E-mail(s) |
daniel.nussbaum@duke.edu
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| Phone |
9196813886
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| Organization name |
Duke University
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| Street address |
203 Research Drive, MSRB1, Room 488
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| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27710 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (42)
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| GSM7596465 |
MIA PaCa-2 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 1 |
| GSM7596466 |
MIA PaCa-2 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 2 |
| GSM7596467 |
MIA PaCa-2 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 3 |
| GSM7596468 |
MIA PaCa-2 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 1 |
| GSM7596469 |
MIA PaCa-2 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 2 |
| GSM7596470 |
MIA PaCa-2 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 3 |
| GSM7596471 |
MIA PaCa-2 cells, control, resistant to SCH772984 (1uM), biological replicate 1 |
| GSM7596472 |
MIA PaCa-2 cells, control, resistant to SCH772984 (1uM), biological replicate 2 |
| GSM7596473 |
MIA PaCa-2 cells, control, resistant to SCH772984 (1uM), biological replicate 3 |
| GSM7596474 |
SW1573 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 1 |
| GSM7596475 |
SW1573 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 2 |
| GSM7596476 |
SW1573 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 3 |
| GSM7596477 |
SW1573 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 1 |
| GSM7596478 |
SW1573 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 2 |
| GSM7596479 |
SW1573 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 3 |
| GSM7596480 |
SW1573 cells, control, resistant to SCH772984 (1uM), biological replicate 1 |
| GSM7596481 |
SW1573 cells, control, resistant to SCH772984 (1uM), biological replicate 2 |
| GSM7596482 |
SW1573 cells, control, resistant to SCH772984 (1uM), biological replicate 3 |
| GSM7596483 |
SW1573 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 1 |
| GSM7596484 |
SW1573 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 2 |
| GSM7596485 |
SW1573 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 3 |
| GSM7596486 |
SW620 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 1 |
| GSM7596487 |
SW620 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 2 |
| GSM7596488 |
SW620 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 3 |
| GSM7596489 |
SW620 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 1 |
| GSM7596490 |
SW620 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 2 |
| GSM7596491 |
SW620 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 3 |
| GSM7596492 |
SW620 cells, control, resistant to SCH772984 (1uM), biological replicate 1 |
| GSM7596493 |
SW620 cells, control, resistant to SCH772984 (1uM), biological replicate 2 |
| GSM7596494 |
SW620 cells, control, resistant to SCH772984 (1uM), biological replicate 3 |
| GSM7596495 |
SW620 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 1 |
| GSM7596496 |
SW620 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 2 |
| GSM7596497 |
SW620 cells, control, treated with SCH772984 (1uM) and Senexin A (1uM) for one week, biological replicate 3 |
| GSM7596498 |
CFPAC1 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 1 |
| GSM7596499 |
CFPAC1 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 2 |
| GSM7596500 |
CFPAC1 cells, control, treated with DMSO (1:1,000) for one week, biological replicate 3 |
| GSM7596501 |
CFPAC1 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 1 |
| GSM7596502 |
CFPAC1 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 2 |
| GSM7596503 |
CFPAC1 cells, control, treated with SCH772984 (1uM) for one week, biological replicate 3 |
| GSM7596504 |
CFPAC1 cells, control, resistant to SCH772984 (1uM), biological replicate 1 |
| GSM7596505 |
CFPAC1 cells, control, resistant to SCH772984 (1uM), biological replicate 2 |
| GSM7596506 |
CFPAC1 cells, control, resistant to SCH772984 (1uM), biological replicate 3 |
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| Relations |
| BioProject |
PRJNA994125 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE237177_Processed_RNA_seq_data.xlsx |
10.0 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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