Panebianco, Federica1; Carty, Sally E.2; Ferris, Robert L.3; Nikiforova, Marina N.1; Nikiforov, Yuri E.1
1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
2 Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, PA, USA
3 Division of Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, USA
Background/Purpose: Papillary thyroid carcinoma development is driven by known point mutations or gene fusions in ~90% of cases, whereas in the remaining tumors the oncogenic driver is unknown (1). Recently, we identified fusions between THADA (chr. 2) and LOC389473 (chr. 7) or other regions upstream of the IGF2BP3 gene in 5% of thyroid cancers and NIFTP lacking other driver mutations and showed that these fusions lead to overexpression of IGF2BP3 and IGF1R signaling (2, 3).
Objectives: The aim of this study was to investigate the role of THADA fusions in thyroid carcinogenesis and targeted therapies for cancer.
Methods: The effects of IGF2BP3 overexpression on cancer cells in vitro were studied using cell proliferation, migration, invasion, and soft-agar colony-formation assays. The effects of IGF1R inhibitor (OSI-906) and MEK inhibitor (Selumetinib) alone and in combination were tested in vitro and in vivo in xenograft tumors in nude mice.
Results: IGF2BP3 overexpression in cultured thyroid and other cancer cells led to increase IGF2 translation and IGF1R signaling via PI3K and MAPK pathways, promoting cell proliferation, invasion and transformation. Inhibition of IGF1R by OSI-906 led to dose-dependent inhibition of IGF2BP3-overexpressing cancer cells growth. In cancer cells with IGF2BP3 overexpression and KRAS mutation, the combination of OSI-906 and Selumetinib led to stronger growth inhibition in vitro and in vivo.
Discussion/Conclusion: THADA fusions to the IGF2BP3 region confer carcinogenic effects on thyroid cells via activating IGF2BP3 and IGF1R signaling. This may be used as a biomarker to predict an anti-IGF1R therapeutic benefit for these patients.
- Cancer Genome Atlas Research N (2014) Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3):676-690.
- Panebianco F, et al. (2017) THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer. Proceedings of the National Academy of Sciences of the United States of America.
- Nikiforov YE, et al. (2016) Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA oncology.