Phosphoglycerate dehydrogenase (PHGDH) was identified as a driver of sorafenib resistance in advanced hepatocellular carcinoma (HCC), and additional preclinical experiments suggest the gene may be a possible target for overcoming sorafenib resistance. The study findings were recently reported in Nature Communications.1
“The underlying mechanisms of sorafenib resistance are complicated and remain largely elusive,” the study authors wrote. “Further investigations on the molecular basis of sorafenib resistance may shed light on the identification of new targets for rational combinational therapy to overcome sorafenib resistance.”
Using genome-wide CRISPR/Cas9 knockout library screening and a sorafenib-resistant HCC cell line, the study researchers identified 984 genes that may potentially contribute to sorafenib resistance in HCC, and the gene that appeared to be the strongest contributor was PHGDH, which contains the instructions for making an important enzyme involved in the serine synthesis pathway.
To confirm this finding, subclones of the sorafenib-resistant HCC cell line were generated in which PHGDH was knocked out, which results in a “mild effect” on cell proliferation. When these cells were exposed to sorafenib, however, cell proliferation was “significantly suppressed.”
Then, in nude mice, tumor growth slowed for PHGDH knockdown tumors upon treatment with sorafenib. In contrast, a second tumor in the mice that had functional PHGDH continued to grow.
To determine whether NCT-503, a PHGDH inhibitor, had synergistic activity with sorafenib, mice were injected with the sorafenib-resistant HCC cell line and treated with sorafenib alone, NCT-503 alone, both drugs together, or vehicle controls. While either drug alone could slow tumor growth, both drugs together “completely halted” tumor growth in mice. When combined with other tyrosine kinase inhibitors (TKI) inhibitors (ie, regorafenib or lenvatinib), NCT-503 showed “profound” apoptotic effects, according to the study authors.
“In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.”
- Wei L, Lee D, Law C-T, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for sorafenib resistance in HCC. Nat Commun. 2019;10(1):4681.