Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer

Elizabeth L. Christie, Swetansu Pattnaik, Jessica Beach, Anthony Copeland, Nineveh Rashoo, Sian Fereday, Joy Hendley, Kathryn Alsop, Samuel L. Brady, Greg Lamb, Ahwan Pandey, Anna deFazio, Heather Thorne, Andrea Bild and David D. L. Bowtell ()
Additional contact information
Elizabeth L. Christie: Peter MacCallum Cancer Centre
Swetansu Pattnaik: Garvan Institute for Medical Research
Jessica Beach: Peter MacCallum Cancer Centre
Anthony Copeland: Peter MacCallum Cancer Centre
Nineveh Rashoo: Peter MacCallum Cancer Centre
Sian Fereday: Peter MacCallum Cancer Centre
Joy Hendley: Peter MacCallum Cancer Centre
Kathryn Alsop: Peter MacCallum Cancer Centre
Samuel L. Brady: The University of Utah
Greg Lamb: The University of Utah
Ahwan Pandey: Peter MacCallum Cancer Centre
Anna deFazio: The Westmead Institute for Medical Research
Heather Thorne: Peter MacCallum Cancer Centre
Andrea Bild: The University of Utah
David D. L. Bowtell: Peter MacCallum Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09312-9

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