Targeting PHGDH upregulation reduces glutathione levels and re-sensitizes resistant NRAS mutant melanoma to MEK inhibition

Melanomas frequently harbor activating NRAS mutations leading to activation of MEK-ERK1/2 signaling; however, clinical efficacy of inhibitors to this pathway are limited by resistance. Tumors re-wire metabolic pathways in response to stress signals such as targeted inhibitors and drug resistance, but most therapeutic resistant pre-clinical models are generated in conditions that lack physiological metabolism. We generated human NRAS mutant melanoma xenografts that were resistant to the MEK inhibitor (MEKi), PD0325901, in vivo . MEKi-resistant (MEKiR) cells showed cross-resistance to the structurally distinct MEKi, trametinib, and elevated ERK1/2 phosphorylation and downstream signaling. Additionally, we observed upregulation of the serine synthesis pathway and phosphoglycerate dehydrogenase (PHGDH), a key enzyme in this pathway. Suppressing PHGDH in MEKiR cells together with MEKi treatment decreased oxidative stress tolerance and cell proliferation. Together, our data suggest targeting PHGDH as a potential strategy in overcoming MEKi resistance.