Therapeutic strategy using novel RET/YES1 dual-target inhibitor in lung cancer
Yong June Choi1, Munkyung Choi1, Jaewoo Park1
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
Lung cancer represents a significant global health concern and stands as the leading cause of cancer-related mortality worldwide. The identification of specific genomic alterations such as EGFR and KRAS in lung cancer has paved the way for the development of targeted therapies. While targeted therapies for lung cancer exhibiting EGFR, MET and ALK mutations have been well-established, the options for RET mutations remain limited. Importantly, RET mutations have been found to be mutually exclusive from other genomic mutations and to be related with high incidences of brain metastasis. Given these facts, it is imperative to explore the development of RET-targeting therapies and to elucidate the mechanisms underlying metastasis in RET-expressing lung cancer cells. In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.
Insights
This study introduces PLM-101, a novel dual-target inhibitor for RET/YES1, showing promise against lung cancer with RET mutations. It effectively combats cancer cell growth and metastasis, offering new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Targeted therapies exist for EGFR, MET, and ALK mutations, but options for RET mutations are limited.
- RET mutations are linked to increased brain metastasis and are mutually exclusive with other genomic alterations.
Purpose of the Study:
- To investigate the efficacy of PLM-101, a novel dual-target inhibitor of RET/YES1.
- To explore the anti-cancer and anti-metastatic potential of PLM-101 in lung cancer.
- To elucidate the role of the YES1-Cortactin-actin remodeling pathway in lung cancer metastasis.
Main Methods:
- Investigated PLM-101, a novel dual-target inhibitor of RET/YES1.
- Assessed anti-cancer activities against CCDC6-RET-positive cancer cells.
- Evaluated anti-metastatic effects against YES1-positive cancer cells.
Main Results:
- PLM-101 demonstrated notable anti-cancer activities against CCDC6-RET-positive cancer cells.
- PLM-101 exhibited significant anti-metastatic effects against YES1-positive cancer cells.
- The study highlighted the YES1-Cortactin-actin remodeling pathway's role in lung cancer cell metastasis.
Conclusions:
- PLM-101 is a promising novel inhibitor targeting both RET and YES1.
- PLM-101 has the potential to impede the growth and metastasis of RET rearrangement lung cancer.
- YES1 is identified as a potential therapeutic target for suppressing lung cancer metastasis.
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