Pin1 inhibitor API-1 sensitizes BRAF-mutant thyroid cancers to BRAF inhibitors by attenuating HER3-mediated feedback activation of MAPK/ERK and PI3K/AKT pathways

by Selleckchem | Nov 15 2023

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.

Comments:

The passage you provided describes a study that investigated the potential therapeutic benefit of a Pin1 inhibitor called API-1 in the context of BRAF-mutant thyroid cancer. Here's a breakdown of the key findings and their implications:

1. **BRAFV600E Mutation**: The BRAFV600E mutation is a genetic alteration commonly found in thyroid cancers. It is a therapeutic target because it drives cancer cell growth and proliferation.

2. **Ineffectiveness of BRAF Inhibitors**: Previous attempts to treat BRAF-mutant thyroid cancers with specific BRAF inhibitors have shown limited clinical benefit. This is because these inhibitors can trigger feedback mechanisms that reactivate the MAPK/ERK and PI3K/AKT signaling pathways, promoting cancer cell survival and growth.

3. **Role of HER3**: The study suggests that the upregulation of HER3, a receptor protein, is responsible for the reactivation of MAPK/ERK and PI3K/AKT pathways in response to BRAF inhibitors. This reactivation undermines the effectiveness of BRAF inhibitors.

4. **Pin1 Inhibitor API-1**: The researchers investigated the use of API-1, a Pin1 inhibitor, in thyroid cancer. Pin1 is a protein involved in tumor progression, and its inhibition is of interest in cancer therapy.

5. **Antitumor Activity of API-1**: The study found that API-1 exhibited strong antitumor activity against thyroid cancer cells. This suggests that targeting Pin1 with API-1 has potential as a therapeutic strategy in thyroid cancer.

6. **Synergy with BRAF Inhibitor**: Importantly, when API-1 was combined with the BRAF inhibitor PLX4032, a synergistic effect was observed. This combination therapy was significantly more effective in inhibiting cancer cell proliferation, colony formation, and tumor growth compared to using API-1 or PLX4032 alone.

7. **Mechanism of Action**: The study delves into the mechanism of action of API-1. It appears that API-1 enhances the ability of XPO5 (exportin 5) to transport pre-microRNA 20a (pre-miR-20a) from the nucleus to the cytoplasm. This promotes the maturation of miR-20a-5p.

8. **Downregulation of HER3**: miR-20a-5p, in turn, specifically targets and downregulates HER3. This action blocks the reactivation of the MAPK/ERK and PI3K/AKT signaling pathways that are typically induced by PLX4032.

9. **Implications**: These results suggest that the combination of Pin1 inhibitor API-1 and BRAF kinase inhibitor PLX4032 could be a promising therapeutic strategy for treating BRAF-mutant thyroid cancer. By targeting Pin1 and inhibiting the reactivation of downstream signaling pathways, this combination therapy overcomes the limitations of BRAF inhibitors alone.

In summary, the study presents evidence that API-1, a Pin1 inhibitor, can enhance the effectiveness of BRAF inhibitors in treating BRAF-mutant thyroid cancer by blocking the reactivation of key signaling pathways. This combination therapy offers a potential new approach for treating this type of cancer.