Abstract
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.
Highlights
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC)
We performed genomewide CRISPR/Cas[9] knockout library screening to identify critical genes involved in Sorafenib resistance in human HCC
NCT-503 worked together with Regorafenib or Lenvatinib to profoundly increase apoptosis in HCC cells (Fig. 6b). These findings suggested that elevation of synthesis pathway (SSP) by up-regulation of phosphoglycerate dehydrogenase (PHGDH), PSAT1, and PSPH is a common mechanism underlying tyrosine kinase inhibitors (TKIs) resistance in HCC and targeting PHGDH may be a promising combinational therapy strategy to improve the efficacy of TKI treatment in HCC patient
Summary
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). the development of drug resistance is common. By using genome-wide CRISPR/Cas[9] library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. High-throughput forward genetic screening approaches have been widely applied to study the molecular mechanisms associated with specific cellular phenotypes, including drug resistance in human cancers. The CRISPR/ Cas[9] library screens have been utilized to identify genes that are important for cancer cell survival, proliferation, migration, and resistance to drug treatment in various models[19,20]. We perform a genome-wide CRISPR/Cas[9] knockout screening in HCC cells with Sorafenib and vehicle control treatments to systematically evaluate the driving mechanisms of Sorafenib resistance.
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