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| Status |
Public on Aug 31, 2018 |
| Title |
Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
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| Overall design |
HCC4006 cells were transfected with NTC, Notch1 or Notch3 siRNAs. Cells split into two groups, one was treated with DMSO and the other was treated with erlotinib for 5 days. Total RNA was collected and subjected to transcriptome analysis.
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| Contributor(s) |
Arasada RR, Zhang J |
| Citation(s) |
30097569 |
| Submission date |
Jun 15, 2018 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Rajeswara Arasada |
| E-mail(s) |
Rajeswara.Arasada@osumc.edu
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| Organization name |
Ohio State University
|
| Street address |
420 W 12th Ave
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43211 |
| Country |
USA |
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| Platforms (1) |
| GPL17586 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA476332 |
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