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 (TVBs) 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.
However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition.
CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs.
In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC.
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This work is supported by grants from 3-V BIOSCIENCES, INC. (YYZ); ACS IRG 85-001-25 (YYZ); NCI K22 CA197193 (YYZ); P20 GM121327 (YYZ); NCI P30 CA177558 (BME); NIDDK U24 DK097215 (TF): NCI R01 CA208343 (BME); NIDDK R01 DK112034 (BME).
Zaytseva, Yekaterina Y.; Rychahou, Piotr G.; Le, Anh-Thu; Scott, Timothy L.; Flight, Robert M.; Kim, Ji Tae; Harris, Jennifer; Liu, Jinpeng; Wang, Chi; Morris, Andrew J.; Sivakumaran, Theru A.; Fan, Teresa; Moseley, Hunter; Gao, Tianyan; Lee, Eun Young; Weiss, Heidi L.; Heuer, Timothy S.; Kemble, George; and Evers, B. Mark, "Preclinical Evaluation of Novel Fatty Acid Synthase Inhibitors in Primary Colorectal Cancer Cells and a Patient-Derived Xenograft Model of Colorectal Cancer" (2018). Toxicology and Cancer Biology Faculty Publications. 71.