Poster Presentation 36th Lorne Cancer Conference 2024

Targeting lipid metabolism to overcome therapy resistance in lethal prostate cancer (#149)

Olivia J Lee 1 , Zhao Qing 2 , Hyungwon Choi 2 , Renea A Taylor 3 , Matthew J Watt 1
  1. The Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
  2. Department of Medicine, National University of Singapore, Singapore
  3. Department of Physiology, Monash University, Melbourne, VIC, Australia

Prostate cancer is the most diagnosed cancer in Australian men. Although there are effective treatments for early-stage localised prostate cancer, one third of patients will progress to an incurable form of the disease known as metastatic castration-resistant prostate cancer (mCRPC). New treatment options are emerging for patients with mCRPC, including Enzalutamide (ENZA), which is an androgen receptor signalling inhibitor. While ENZA extends patient survival, ENZA-resistance commonly occurs. Prostate tumours are highly lipogenic, and rely on lipid biosynthesis for cancer cell survival, yet little is known about how reprogrammed lipid metabolism contributes to acquired ENZA resistance.

To determine if dysregulated lipid metabolism contributes to the development of ENZA-resistance, we performed untargeted proteomics and untargeted lipidomics in two prostate cancer cell lines: C4-2B cells (ENZA-sensitive) and MR49F cells (ENZA-resistant). Using tandem mass spectrometry (LC-MS/MS) we detected >7,500 proteins across both cell lines, with 1,405 proteins that were significantly upregulated and 1,167 proteins that were significantly downregulated in ENZA-resistant cells compared with ENZA-sensitive cells. Untargeted lipidomic analysis detected ~600 unique lipid species in both cell lines. Multi-omic integration analysis revealed several lipid species and lipid-related processes that were dysregulated in ENZA-resistant prostate cancer cells compared with ENZA-sensitive cells.

Elevated acylcarnitine (CAR) levels were detected in ENZA-resistant prostate cancer cells, along with reduced expression of the transporter SLC25A20 that facilitates the import of CAR into mitochondria for oxidation. Additionally, cholesterol ester (CE) abundance and the expression of cholesterol biosynthetic enzymes were notably reduced in ENZA-resistant cells. Expression of several enzymes involved in fatty acid chain elongation were suppressed in ENZA-resistant cells, which was associated with enrichment of short/medium-chain fatty acids and depletion of long-chain fatty acids across multiple key lipid classes.

These data demonstrate that lipid metabolism is reprogrammed in ENZA-resistant prostate cancer. Our study has identified several potential metabolic dependencies, including CE metabolism, CAR metabolism and fatty acid chain elongation, that could be targeted to improve the effectiveness of ENZA for patients with prostate cancer.