A Combinatorial Strategy for Tageting Papillary Thyroid Carcinoma with MEK Inhibitor and SHP2 Inhibitor

Background: Pharmacologic targeting of components of MAPK/ERK pathway in thyroid carcinoma is often limited due to the development of adaptive resistance. However, the detailed mechanism for MEK inhibitor (MEKi) resistance is not fully understood in papillary thyroid carcinoma (PTC). Methods: RNA-seq was performed in MEKi-resistant PTC cell lines (K1, BCPAP, TPC-1 and KTC-1) to investigate the intrinsic mechanism of drug resistance. Colony formation assay, cell viability assay, cell cycle analysis and various murine models, including xenograft model, long-term MEKi-treated model, and transgenic model were conducted to evaluate the treatment effect of combination therapy (SHP099 and selumetinib). Results: Multiple receptor tyrosine kinases (RTKs) signaling pathways as well as Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream of many RTKs, we first found that blockage of SHP2 abrogated MEKi resistance in thyroid cancer. Interestingly, we also found MEKi in combination with SHP2 inhibitor remarkably suppress rebound of MEK/ERK pathway compared to that of MEKi treatment alone, which significantly improved antitumor effects of MEKi. Various murine models confirmed the synergistic suppression on PTC in mice treated with both inhibitors. Conclusion: SHP2 blockade by SHP099 in combination with selumetinib is a promising therapeutic approach for advanced thyroid cancer.

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