A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance

Xin Li; Zixiong Wang; Chao Chen; Fan Yang; Ping Liu; Shu Fang; Bin Wang; Shi Chen; Xinjian Li

doi:10.1016/j.isci.2024.109015

A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance

iScience. 2024 Jan 26;27(2):109015. doi: 10.1016/j.isci.2024.109015. eCollection 2024 Feb 16.

Authors

Xin Li^{1

2}, Zixiong Wang^{1

2}, Chao Chen¹, Fan Yang^{1

2}, Ping Liu¹, Shu Fang^{1

2}, Bin Wang^{1

2}, Shi Chen^{3

4}, Xinjian Li^{1

2}

Affiliations

¹ Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
² College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
³ Department of Gastric Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
⁴ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.

Abstract

Anaplastic lymphoma kinase (ALK) is a highly responsive therapeutic target for ALK-rearranged non-small cell lung cancer (NSCLC). However, patients with this cancer invariably relapse because of the development of ALK inhibitor resistance resulting from mutations within the ALK tyrosine kinase domain. Herein, we report the discovery of dEALK1, a small-molecule degrader of EML4-ALK fusion proteins, with capability of overcoming resistance to ALK inhibitor ceritinib. dEALK1 induces rapid and selective degradation of wild-type (WT) EML4-ALK and mutated EML4-ALKs acquiring resistance to ceritinib, leading to inhibition of cell proliferation and increase of apoptosis in NSCLC cells expressing WT EML4-ALK or ceritinib-resistant EML4-ALK mutants in vitro. Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

Keywords: Biochemistry; Biological sciences; Cancer; Cell biology; Natural sciences; Pharmacology.