Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30894541.
- Also identified by DOI 10.1038/s41467-019-09312-9 and PMC identifier 6426934.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.
Medical subject headings
- Breast Neoplasms
- Cystadenocarcinoma, Serous
- Drug Resistance, Neoplasm
- Gene Expression Regulation, Neoplastic
- Oncogene Proteins, Fusion
- Ovarian Neoplasms