New understanding of how lung cancer cells become more aggressive when nutrient deprived could lead to novel combination treatments.

Lung cancer cells (green) are cultured together with normal lung cells (red). The triple-antibody combination EGFR, HER2 and HER3 strongly impairs the survival of tumor cells while sparing normal cells. Modified confocal microscopy image: Maicol Mancini, lab of Professor Yosef Yarden. CREDIT: Weizmann Institute of Science.

Inhibiting glycolysis

Cancer cells are highly dependent on sugar, particularly glucose, to grow and divide. Inhibiting or preventing this process, known as glycolysis, has been studied by scientists for a while as a potential strategy against cancer. Researchers from the UCLA Health Jonsson Comprehensive Cancer Center have previously found a specific protein sodium glucose transporter 2 (SGLT2), as a mechanism that lung cancer cells can use to acquire glucose. Drugs that inhibit SGLT2 are already FDA approved for other conditions and the UCLA team discovered that these drugs could also slow the development of lung cancer. When tested in mice, these drugs improved survival, suggesting these drugs could be repurposed for lung cancer treatment.

However, the scientists discovered that whilst inhibiting glycolysis can slow down the growth of tumours, it can also make cancer cells more aggressive, making the cancer more difficult to treat. Therefore, the team investigated other mechanisms of resistance in the tumours that still grow while being treated with SGLT2 inhibition that may link glucose restriction to increases aggression.

Aggressive cancer cells

The study found that lung cancer cells lost their specialised features when glucose was restricted, making them more aggressive. This change was linked to alterations in specific molecules and how they modify DNA structure. One of those molecules, alpha-ketoglutarate, is important for both in energy metabolism and in gene regulation. Reduced levels of alpha-ketoglutarate affected how genes are turned on and off, activating HIF1α, a transcription factor known to be involved in making cancer cells more aggressive.

This then led the team to find a certain set of genes, controlled by HIF1α, that could predict how aggressive a cancer might be. This will provide physicians with important information to help guide treatment decisions. They also discovered potential ways to block the tumour from becoming more aggressive when nutrient deprived.

Dr Claudio Scafoglio, senior author of the study and Assistant Professor of Pulmonary and Critical Care Medicine at UCLA, explained: “While we still need to further explore the intricacies of this mechanism, our findings point to a potential therapeutic strategy using a combination of treatments involving epigenic modulators or HIF inhibitors to counter the unintended effects of glucose restriction.” Dr Scafoglio is also a member of the UCLA Health Jonsson Comprehensive Cancer Center.

 Combination approach

The study offers an essential understanding of the role of glucose restriction in causing an aggressive phenotype in lung cancer. These new insights suggest a novel possible combination approach to treat early-stage lung cancer, using a glucose inhibitor and an epigenetic inhibitor that are already available for other conditions, which can help reduce tumour growth and offset aggressive behaviour.

Currently, further research is taking place to find the correct approach to prevent starvation-induced de-differentiation without causing substantial side effects.

The study was published in the journal Cancer Research.