Anlotinib suppresses lung adenocarcinoma growth via inhibiting FASN-mediated lipid metabolism

Juan Shen; Jie Huang; Yu Huang; Yidan Chen; Jiawei Li; Peihua Luo; Qianyun Zhang; Yao Qiu; Lie Wang; Hong Jiang; Shenglin Ma; Xueqin Chen

doi:10.21037/atm-22-5438

Anlotinib suppresses lung adenocarcinoma growth via inhibiting FASN-mediated lipid metabolism

Ann Transl Med. 2022 Dec;10(24):1337. doi: 10.21037/atm-22-5438.

Authors

Juan Shen^#^{1

2}, Jie Huang^#², Yu Huang³, Yidan Chen², Jiawei Li², Peihua Luo⁴, Qianyun Zhang⁵, Yao Qiu², Lie Wang⁶, Hong Jiang⁷, Shenglin Ma^{1

2

8}, Xueqin Chen^{1

2

8}

Affiliations

¹ Department of Thoracic Oncology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
⁴ Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
⁵ Department of Oncology, Liyang People's Hospital, Liyang, China.
⁶ Institute of Immunology and Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁷ Department of Thoracic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ Cancer Center, Zhejiang University, Hangzhou, China.

^# Contributed equally.

Abstract

Background: Anlotinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, has been widely used in advanced lung cancer patients, but the intrinsic mechanism of cancer cell elimination is not fully disclosed. In this study, we reported that anlotinib suppressed lung adenocarcinoma (LUAD) growth through inhibiting fatty acid synthase (FASN)-mediated lipid metabolism.

Methods: To investigate the underlying mechanisms of anlotinib, an A549 cell line-derived xenograft model was constructed and a proteomics technique was employed to screen potential markers. Gas chromatography-mass spectrometry (GC-MS) profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining were employed to detect lipid metabolism in cancer cells. Subsequently, the effects of anlotinib on FASN expression were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Short hairpin RNA (shRNA) knockdown of FASN was used to assess the role of FASN in the antitumor effect of anlotinib. A patient-derived xenograft (PDX) model was established to validate the efficacy of anlotinib in the patient and IHC staining of FASN was examined.

Results: Our data revealed that anlotinib significantly decreased the expression of proteins related to lipid metabolism. GC-MS profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining validated that anlotinib could disturb the fatty acid metabolism in cancer cells, especially de novo lipogenesis. Mechanically, the messenger RNA (mRNA) and protein of FASN were down-regulated by anlotinib in A549 cells and FASN knockdown could diminish the antitumor effect of anlotinib in vitro. Remarkable tumor shrinkage by anlotinib was further shown in a patient with multiple-line treatment failure, and FASN reduction was evidenced in the corresponding patient-derived xenograft (PDX) model.

Conclusions: Anlotinib could inhibit the growth of LUAD through FASN-mediated lipid metabolism. Our findings provide new insights into the antitumor mechanism of anlotinib in lung adenocarcinoma.

Keywords: Anlotinib; fatty acid synthase (FASN); lipid metabolism; lung adenocarcinoma.