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  3. Therapeutic strategy using novel RET/YES1 dual-target inhibitor in lung cancer

Therapeutic strategy using novel RET/YES1 dual-target inhibitor in lung cancer

  • Biomed Pharmacother. 2024 Jan 9:171:116124. doi: 10.1016/j.biopha.2024.116124.
Yong June Choi 1,  Munkyung Choi 1,  Jaewoo Park 1,  Miso Park 2,  Myung Jun Kim 1,  Jae-Sun Lee 3,  Su-Jin Oh 3,  Young Joo Lee 1,  Wan Seob Shim 1,  Ji Won Kim 4,  Myung Jin Kim 3,  Yong-Chul Kim 5,  Keon Wook Kang 6
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Department of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea.
  • 3 R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea.
  • 4 Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea.
  • 5 R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 6 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
PMID: 38198957 DOI: 10.1016/j.biopha.2024.116124
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.

Keywords

CCDC6-RET; Dasatinib (PubChem CID: 3062316); Lung cancer; Metastasis; Osimertinib (PubChem CID: 71496458); PLM-101 (no PubChem CID); RET/YES1 dual-target inhibitor; YES1-Cortactin-actin remodeling pathway.

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