Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways
Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger
Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger
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Research Article Cell biology Metabolism

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

Abstract

Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity.

Authors

Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger

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Figure 2

SH-BC-893 selectively kills cancer cells.

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SH-BC-893 selectively kills cancer cells. (A) Viability of FL5.12 cells ...
(A) Viability of FL5.12 cells cultured in control medium (500 pg/ml IL-3) or adapted to low IL-3 (25 pg/ml) treated with 5 μM FTY720 or SH-BC-893. (B) Bound NADH fraction in FL5.12 cells cultured as in A and treated with FTY720 or SH-BC-893. (C) Viability of the indicated cells treated with 5 μM SH-BC-893 for 72 hours. Statistical significance was compared with vehicle. OP9 (murine bone marrow stromal cells), and primary MEF were nontransformed cells. DLD-1, LS180, SW480, SW480, and SW620 were colon cancer cell lines. MDA-MB-231 and PANC-1 were breast cancer and pancreatic cancer cell lines, respectively. (D) Bound NADH fraction in control or KrasG12D-expressing MEFs treated with 1 mM 2-DG, starvation media (glucose and amino acids supplemented with 10% dialyzed FCS), or 7.5 μM SH-BC-893 for 16 hours. Statistical significance was compared with respective controls. (E) Viability of p53–/– MEFs, with or without KrasG12D expression, that were treated with 6 μM SH-BC-893. (F) Colony formation by normal human PBMCs or SW620 CRC cells, with or without SH-BC-893 at the indicated doses. Error bars indicate the mean ± SEM. (G–I) Subcutaneous SW620 tumor growth as measured by bioluminescence imaging (BLI) (G), calipers (H), or tumor weight at sacrifice (I). Because FTY720 and SH-BC-893 were similarly potent in vitro (Figure 1, C and E) (26), SH-BC-893 was given i.p. at a dose of 10 mg/kg for 7 days. On the basis of BLI (G), the dose was increased to 20 mg/kg on day 8. Error bars indicate the mean ± SD. n = 7 mice per group. *P <0.05, **P <0.01, and ***P <0.001, by unpaired, 2-tailed Student’s t test. P values were determined using Tukey’s method when correcting for multiple comparisons. In vitro data are representative of at least 3 independent experiments.