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.
Highlights
ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs
Our previous whole-genome analysis of post-treatment high-grade serous ovarian cancer (HGSC) and breast cancer samples identified a transcriptional fusion between ABCB1 and the upstream gene SLC25A40 associated with up-regulation of ABCB1 expression, while leaving the predicted MDR1 protein unaltered[1,2]
We considered whether tumours with a propensity to undergo structural rearrangement may be more likely to have fusion events, but we found no indication of an association between the frequency of Structural variants (SV) in a sample and ABCB1 fusion positivity (Fig. 2c)
Summary
ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. 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. Convergent evolution of ABCB1 fusion is frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi. Our previous whole-genome analysis of post-treatment high-grade serous ovarian cancer (HGSC) and breast cancer samples identified a transcriptional fusion between ABCB1 and the upstream gene SLC25A40 associated with up-regulation of ABCB1 expression, while leaving the predicted MDR1 protein unaltered[1,2]. We sought to determine the frequency and circumstances in which ABCB1 fusions arise in a large cohort of recurrent HGSC and a smaller series of breast cancer patients
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