Type I interferons modulate methotrexate resistance in gestational trophoblastic neoplasia
Kevin M Elias1, Richard A Harvey2, Kathleen T Hasselblatt1
1New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Problem:
Resistance to methotrexate is a leading clinical problem in gestational trophoblastic neoplasia (GTN), but there are limited laboratory models for this condition.
Method Of Study:
We created isogenic trophoblastic cell lines resistant to methotrexate and compared these to the parent cell lines using gene expression microarrays and qRT-PCR followed by mechanistic studies using recombinant cytokines, pathway inhibitors, and patient sera.
Results:
Gene expression microarrays and focused analysis by qRT-PCR revealed methotrexate led to type I interferon upregulation, in particular interferon alpha 2 (IFNA2), and methotrexate resistance was associated with chronic low level increases in type I interferon expression. Recombinant IFNA2 imparted chemosensitive choriocarcinoma cells with partial resistance to methotrexate, while chemoresistant choriocarcinoma cells were uniquely sensitive to fludarabine, a STAT1 inhibitor. In pre-treatment patient sera, IFNA2 levels correlated with subsequent resistance to methotrexate chemotherapy.
Conclusion:
Methotrexate resistance is influenced by type I interferon signaling with prognostic and therapeutic implications for treating women with GTN.
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