Bioenergetics of lung cancer predicts treatment response and adaptive capacity

Background: Lung cancer is one of the most common cancers with the highest cancer-related mortality. Life expectancy remains limited, and recurrence is common. Treatment regimens aim to eradicate tumors. However, during the treatment course, resistance occurs in specific niches with metabolic peculiarities owing to molecular alterations that induce bioenergetic adaptations to enable survival, allowing recurrence. Metabolic adaptations for survival are well known, but their related bioenergetics mechanisms are not fully understood. Methods: Two non-malignant and four cancer commercial cell lines were used under conditions of immediate metabolic starvation (IMS), long-term starvation (LTS, a single substrate for 30 days without medium change), or cisplatin and metabolic inhibition treatments (up to 72 h) to determine the bioenergetics mechanisms of survival. Results: Under culture conditions, lung cells use a similar proportion of oxygen for each respiratory parameter, but this proportion changes under IMS conditions, reflecting the metabolic state of the cells. Selection occurs after 10 days of LTS, and the spare respiratory capacity (SRC) under IMS is maintained after this selection period. Under LTS, cancer cells increased their proliferation and reduced viability, while viability and proliferation of non-malignant cells were unaffected. After LTS, surviving cells were enriched with cancer like-stem cells, maintaining aggressiveness, especially under glucose selection. Cells with higher SRC values were more resistant to cisplatin. Cancer resistance is counteracted by dual metabolic glycolysis and OxPhos inhibition. Conclusions: We argue that survival mechanisms depend on SRC, including resistance, and that SRC can predict treatment response to platinum-based treatment.