Identification of the Serine Biosynthesis Pathway as a Critical Component of BRAF Inhibitor Resistance of Melanoma, Pancreatic, and Non-Small Cell Lung Cancer Cells

Molecular Cancer Therapeutics
Kayleigh C RossVikram Bhattacharjee

Abstract

Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFi). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA-damaging drug gemcitabine, we show that gemcitabine pretreatment sensitized resistant melanoma cells to BRAFis vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pretreatment of pancreatic cancer and non-small cell lung cancer cell lines with sublethal doses of 50 and 5 nmol/L of gemcitabine, respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gem...Continue Reading

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