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The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes
Francesca Carlomagno1, Donata Vitagliano, Teresa Guida
1Centro di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, 80131 Naples, Italy. persfra@tin.it
Abstract:
Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 microM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms.
Insights
The pyrazolo-pyrimidine PP1 effectively inhibits RET oncoproteins, crucial in many cancers. This compound shows promise for treating RET-associated cancers by halting tumor cell growth and reversion.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Oncogenic activation of the RET receptor tyrosine kinase is a frequent event in various human cancers.
- RET rearrangements are implicated in the development and progression of several neoplasms.
Purpose of the Study:
- To investigate the inhibitory effects of the pyrazolo-pyrimidine PP1 on RET-derived oncoproteins.
- To evaluate the therapeutic potential of PP1 in preclinical models of RET-associated cancers.
Main Methods:
- In vitro kinase inhibition assays to determine the half maximal inhibitor concentration (IC50) of PP1 against RET oncoproteins.
- Cell-based assays to assess the impact of PP1 on the proliferation, morphology, and anchorage-independent growth of cancer cells.
- In vivo tumorigenicity studies in nude mice using NIH3T3 fibroblasts expressing RET/PTC3.
Main Results:
- PP1 demonstrated potent inhibition of RET-derived oncoproteins with an IC50 of 80 nM.
- Treatment with PP1 (5 microM) led to loss of proliferative autonomy and morphological reversion in RET/PTC3-transformed cells.
- PP1 inhibited the growth of human papillary thyroid carcinoma cell lines with RET/PTC1 rearrangements.
- PP1 blocked anchorage-independent growth and reduced tumorigenicity in vivo.
Conclusions:
- PP1 is a potent inhibitor of RET oncoproteins and exhibits anti-cancer activity in preclinical models.
- Targeting RET oncogenes with PP1 or similar compounds represents a potential novel therapeutic strategy for RET-associated neoplasms.