Tumor hypoxia promotes MAPK signaling by inhibiting prolyl hydroxylation of SOS1

Abstract The hypoxic tumor microenvironment promotes both cancer progression and drug resistance.Prolyl hydroxylases are hypoxic sensor proteins that are frequently mutated or heterozygously deleted in breast cancers; however, how prolyl hydroxylation regulates breast cancer progression and drug resistance remains poorly understood. Here, we found that hypoxia promotes cancer progression and resistance to chemotherapy drugs, specifically through prolyl hydroxylation-dependent activation of MAPK signaling. We characterized a pVHL-independent mechanism wherein the prolyl hydroxylase EglN1 catalyzed prolyl hydroxylation of the proline-rich domain of RAS-specific guanine nucleotide exchange factor SOS1, thereby preventing its binding with the growth factor receptor bound protein 2 (GRB2) to block the formation of MAPK signaling microclusters in breast cancer. Inhibition of EglN1’s prolyl hydroxylase function—which occurs in hypoxic conditions and upon accumulation of fumarate—induced cancer-specific dysregulation of MAPK signaling, which promoted both breast cancer growth and resistance to MEK inhibitors. We harnessed this insight and demonstrated a therapeutic strategy that potently inhibits breast cancer growth and drug resistance based on pharmacologically disrupting the prolyl-hydroxylation-mediated interaction between SOS1 and GRB2.