Abstract 452: Activation of Akt pathway and autophagy promotes resistance to FASN inhibition in colorectal cancer patient-derived xenograft models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.452-452
• Main Authors: Zaytseva, Yekaterina Y., Rychahou, Piotr G., Le, Anh-Thu, Flight, Robert M., Scott, Timothy L., Harris, Jennifer W., Hodges, Sally, Hallahan, Brent J., Napier, Dana L., Liu, Jinpeng, Wang, Chi, Sunkara, Manjula, Morris, Andrew, Kim, Ji Tae, Arumugam, Sivakumaran Theru, Lane, Andrew, Fan, Teresa W., Moseley, Hunter, Gao, Tianyan, Lee, Eun Y., Weiss, Heidi L., Heuer, Timothy S., Kemble, George, Evers, B Mark
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-452

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial in solid tumor patients. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. The purpose of our study was: (i) to determine the effect of FASN inhibition on tumor growth in CRC patient-derived xenografts (PDXs); (ii) to identify potential biomarkers associated with CRC responsiveness to FASN inhibition; and (iii) to explore new combination strategies with FASN inhibitors. METHODS. Tumor growth was assessed in 9 PDXs established in NSG mice using freshly resected specimens. Once the xenografts grew to ~100 mm3, mice were randomized into two groups (n=5) to receive either vehicle or TVB-3664 or four groups (n=10) for TVB-3664 treatment in combination with either MK2206 or Chloroquine (CQ). Tumor volume and animal weights were measured weekly. Western blot analysis and immunohistochemistry staining were used to identify FASN-mediated changes in signaling pathways. Changes in metabolites and lipids were analyzed by nuclear magnetic resonance and mass spectrometry in plasma and tumor tissues. Next Generation Sequencing was used to assess the mutation profile of 198 oncogenes in patient tumors and PDXs. RESULTS. PDXs showed a wide range of sensitivity to FASN inhibition: TVB-3664 treatment attained significant response (reduced tumor volume) in 3 PDXs, significant response followed by developed resistance in one PDX, and no response in 5 PDXs. Activation of Akt and AMPK pathways was associated with resistance to FASN inhibition and combination of TVB-3664 with either MK2206 or CQ led to a significant reduction in tumor volume as compared to either drug alone. Moreover, TVB-3664 treatment significantly decreased the total palmitate level in plasma and the levels of triglycerides, diglycerides, phosphatidylserines, phosphatidylethanolamines, and phosphatidylcholines in tumor tissues. Furthermore, a significant decrease in the levels of AXP-1, AXP-2 and myo-Inositol-2 was observed in tumors responsive to FASN inhibition. CONCLUSIONS. Our studies demonstrate that TVB-3664 shows anti-tumor activity in CRC. Importantly, our results suggest that activation of Ak