Bioenergetics of lung cancer cells as a predictor of treatment response and adaptive capacity.

Background Lung cancer is the third most incident but the deadliest type of cancer. This is due to its late diagnosis because of its asymptomatic behavior in early stages and resistance to different treatments. In addition, 50% of patients treated with (neo)adjuvant therapy and/or surgery relapse within five years of the intervention. Relapse depends on cell survival, and very little is known about this process. Cancer cells must adapt their bioenergetics during selection pressures, such as tumor growth or treatments, to survive. For this reason, we aim to understand the bioenergetics mechanisms of lung cancer survival.

Methods & Materials We used six commercial cell lines: two from normal lung fibroblasts (MRC-5 and WI38) and four from non-small cell lung cancer -NSCLC- (A549, NCI-H23, H1299 and H460). Bioenergetics patterns were obtained by high-resolution respirometry in paired experiments under culture conditions and immediate starvation.

Results Culture conditions showed no respirometric differences between cell lines, but immediate starvation showed two different patterns: cells with high and cells with low maximal respiration, conferring high and low spare capacity ([maximal – routine] respiration), respectively. This means that the first group of cells are anabolically active producing endogenous substrate that can be used for proliferation or survival, and the second, catabolically active cells consuming nutrients for survival and/or proliferation. We then treated the cell lines with cisplatin for up to 72h, and the pattern of response correlated with the spare capacity: those with high spare were more resistant to treatment. Next, we tried to induce metabolic adaptation by culturing the cells for 30 days on different individual substrates without any media change, forcing the cells to adapt or die. Cells that showed higher spare capacity in the initial experiments also showed higher adaptability to long-term starvation and survived some conditions. Thus, we observed that normal cells survive in the presence of any metabolic substrate, whereas cancer cells with a higher spare capacity survive some conditions better.

Conclusion This suggests that normal and cancer cells exhibit different molecular mechanisms of survival, and that the spare capacity can be used to predict the survival of lung cancer cells to selection pressures under experimental conditions. Similar applicability in cancer patients could be tested to open new avenues in oncological research.

 

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Publication History

Article published online:
25 August 2025