BRAFV600E mutation is one of the most therapeutic targets in
thyroid cancers. However, its specific inhibitors have shown little clinical benefit because they can reactivate the MAPK/ERK and PI3K/AKT pathways by feedback upregulating the transcription of HER3.
Peptidyl-prolyl cis/trans isomerase Pin1 has been proven to be closely associated with
tumor progression. Here, we aimed to determine antitumor activity of Pin1 inhibitor API-1 in
thyroid cancer and its effect on cellular response to BRAF inhibitors. The results showed that API-1 exhibited strong antitumor activity against
thyroid cancer. Meanwhile, it improved the response of BRAF-mutant
thyroid cancer cells to BRAF inhibitor
PLX4032 and there was a synergistic effect between them. Specially, a combination
therapy of API-1 and
PLX4032 significantly inhibited cell proliferation, colony formation, and the growth of xenograft
tumors as well as induced cell apoptosis in BRAF-mutant
thyroid cancer cells compared with API-1 or
PLX4032 monotherapy. Similar results were also observed in transgenic mice with BrafV600E-driven
thyroid cancer. Mechanistically, API-1 enhanced XPO5 ability to export pre-
microRNA 20a (pre-miR-20a) from the nucleus to cytoplasm, thereby promoting the maturation of miR-20a-5p. Further studies showed that miR-20a-5p specifically targeted and down-regulated HER3, thereby blocking the reactivation of MAPK/ERK and PI3K/AKT signaling pathways caused by
PLX4032. These results, taken together, demonstrate that Pin1 inhibitor API-1 significantly improves the sensitivity of BRAF-mutant
thyroid cancer cells to
PLX4032. Thus, this study not only determines the potential antitumor activity of Pin1 inhibitor API-1 in
thyroid cancer but also offers an alternative therapeutic strategy for BRAF-mutant
thyroid cancers by a combination of Pin1 inhibitor and
BRAF kinase inhibitor.