A non-canonical glucose metabolic rewiring enables resistance to cancer targeted therapy

Targeting glucose metabolism for cancer therapy is a long-lasting pursuit but with disappointing translational success. Revelation of actionable distinctions between the malignancy traits to achieve selectivity is a prerequisite for fulfilling a therapeutic window. We discover a non-canonical glucose transporter GLUT6-facilitated, lactate-independent, glucose metabolic rewiring that selectively enables resistance to targeted therapy in lung cancer. Downstream, GLUT6 facilitated glucose influx and straying to methylglyoxal which dimerized KEAP1 and upregulated NRF2 pathway to confer resistance. Upstream, GLUT6 was transcriptionally upregulated by therapy-induced MAZ activation. Targeting GLUT6 prevented and overcame resistance to EGFR and KRAS inhibitors and the MAZ-GLUT6-NRF2 signaling correlated with clinical therapy response and relapse. Our findings uncover an unrecognized non-genetic, metabolic mechanism for drug resistance and a scenario specifically determined by a distinct glucose metabolic rewiring in cancer. The preferential dependance of the non-canonical, general-homeostasis-less-perturbing transporter GLUT6 implies a promise for resistance overcoming and for glucose metabolism-targeting strategy, two long and urgent quests.