GLUCOSE DEPENDENCE AND METABOLIC FLEXIBILITY ARE KEY RESPONSE DETERMINANTS TO A NOVEL SMALL MOLECULE OXPHOS INHIBITOR

Abstract

Nasopharyngeal cancer (NPC) has limited treatment response upon recurrence. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been observed in various cancers, including NPC, and results in increased tumour aggressiveness. OPB-51602 (OPB), a small-molecule inhibitor of STAT3 phosphorylation, exhibited significant tumour response in NPC patients in Phase I trials. In vitro, however, inhibition of STAT3 phosphorylation was inconsistent and inconclusive. Concurrent monitoring reported increased acidosis in patients, hinting at mitochondrial oxidative phosphorylation (OXPHOS) inhibition by OPB. Subsequent work validated Complex I-specific inhibition of OPB regardless of sensitivity. Analysis of compensatory resistance mechanisms towards OPB treatment identified an upregulation of P-T180/Y182 p38α, the inhibition of which modestly re-sensitized OPB-resistant cells. Strikingly, distinct innate fuel dependencies and metabolic (in)flexibility correlated with OPB response, the targeting of which could be explored to sensitize OPB-resistant NPC cells. Our findings highlight the importance of metabolic profiling in drug resistance and response.