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Targeting Platinum Resistant Lung Cancer by Exploiting Metabolic Differences
Location: 48
Mentor: Dr. Medhi Wangpaichitr
Cisplatin resistance (CR) remains a major challenge in lung cancer treatment. We identified increased ROS levels as a common feature in CR lung cancer cells, linked to metabolic reprogramming and immune evasion. CR cells do not primarily utilize glucose, but rather rely on amino acids like glutamine and tryptophan for survival, consuming twice as much glutamine (n=4, p<0.05) and tryptophan (n=4, p<0.04) compared to parental counterparts. Under oxidative stress, CR cells activate the kynurenine pathway, a key tryptophan catabolism route.
Extracellular kynurenine promotes immunosuppressive regulatory T cells (Tregs). Using in vitro co-culture models (n=6), we found that IDO1-mediated kynurenine production in CR cells suppresses NKG2D on NK and CD8+ T cells while enhancing Tregs and MDSCs. In a syngeneic C57B6 mouse model, IDO1 inhibition reduced tumor growth in CR tumors but induced tryptophan 2,3-dioxygenase-2 (TDO2), suggesting a compensatory response.
To counteract this, we tested a novel dual IDO1/TDO2 inhibitor (AT-0174), which suppressed tumor growth more effectively than IDO1 inhibition alone. Dual inhibition significantly increased immune effector populations while reducing Tregs and MDSCs in CR tumors.
These findings suggest that TDO2 compensates for IDO1 inhibition, potentially explaining the failure of epacadostat in the ECHO-301 trial. Our results highlight the therapeutic potential of dual IDO/TDO inhibition as an immunotherapy strategy, enhancing tumor immune surveillance and blocking metabolic survival mechanisms in platinum-resistant NSCLC.
