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| Status |
Public on Mar 04, 2019 |
| Title |
MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance (miRNA-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Non-coding RNA profiling by high throughput sequencing
|
| Summary |
CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor (ER)-positive breast cancer, so that defining mechanisms of resistance is a pressing issue. Here, we identify increased CDK6 expression as a key determinant of acquired resistance after exposure to palbociclib in ER-positive breast cancer cells. Increased CDK6 in resistant cells was dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediated transfer of the resistance phenotype between neighboring cell populations. We confirmed these data in pre-treatment and post-progression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating clinical relevance of this mechanism. Additionally, the CDK4/6 inhibitor resistance phenotype can be reversed in vitro and in vivo by a prolonged drug holiday.
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| Overall design |
We performed miRNAseq in 44 tumor biopsies taken from patients who received CDK4/6 inhibitor treatment. Samples were grouped based on the patients response into sensitive (S), inherent (IR) or aquired (AR) CDK4/6 inhibitor resistance.
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| |
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| Contributor(s) |
Cornell L, Shapiro. GI |
| Citation(s) |
30840889 |
| |
| Submission date |
Jul 26, 2018 |
| Last update date |
Apr 17, 2019 |
| Contact name |
Liam Cornell |
| E-mail(s) |
liam_cornell@dfci.harvard.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Street address |
450 brookline avenue
|
| City |
boston |
| State/province |
MASSACHUSETTS |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (45)
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| This SubSeries is part of SuperSeries: |
| GSE117748 |
MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance |
|
| Relations |
| BioProject |
PRJNA483061 |
| SRA |
SRP155416 |
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