Lung cancer has been strongly associated with cigarette smoking, since at least the 1960s. While smoking is still the leading cause of lung cancer cases worldwide, it is far from the only factor. A recent concerning trend is the rise in lung cancer among non-smokers.
Among non-smokers, a combination of factors is responsible for elevated lung cancer risk. Long-term exposure to air pollution is a major concern, particularly in Asia. Occupational exposure to carcinogens can also play a role.
The final piece in the puzzle is genetics. The presence of specific mutations in your DNA can influence several things, including overall cancer risk, the rate of tumor growth, and resistance to treatment.
A great example is the Anaplastic Lymphoma Kinase (ALK) gene. Along with the EGFR gene, mutated ALK has been noted in around 15% of all non-small cell lung cancers (NSCLCs) among Caucasian patients.
Among non-smokers who develop lung cancer, ALK has been identified as one of the three most clinically relevant mutations. The other two are EGFR and KRAS. In general, these mutations are more common in younger lung cancer patients who have no history of cigarette use.
In its healthy state, ALK plays an important role in cell growth and neural development. Similarly, in their mutated form, oncogenes like ALK also play a central role in facilitating the uncontrolled growth and spread of cancer cells.
Improving our understanding of these cellular mechanisms could help us develop more effective cancer therapies and drugs. In an exciting new study published in Cell, a team from Harvard Medical School has taken a major step forward in this direction.
The Significance of Cell Metabolism in Lung Cancer Research
Lung cancer is the leading cause of cancer death among humans, claiming over 1.8 million lives each year worldwide (2020 WHO figures). There are several reasons for this:
- Due to mild initial symptoms, most cases are discovered in stages III and IV, reducing treatment success rates
- Identifying high-risk individuals through screening protocols is not easy (except in the case of heavy smokers)
- Small cell lung cancers (SCLC) are very aggressive and can grow and spread to other organs in a matter of weeks after diagnosis
- Non-small cell lung cancers (NSCLC) have high genetic instability and mutation burden, making them more resistant to treatment
Cell metabolism plays a central role in the aggressive growth of cancer cells. This is why it is a topic of vital interest in the realm of cancer research, particularly when it comes to lung cancer.
The ALK is an Excellent Candidate for Targeted Therapies
Although exceptions do exist, lung cancers tend to not respond well to traditional chemotherapy. For NSCLC, the response rate is usually around 30%, while small cell lung cancers may initially respond, only to develop resistance in later stages of the treatment.
ALK-positive lung cancers have a better outlook in comparison when treated with targeted therapies, due to the following key reasons:
- ALK-positive cancers do respond well to a particular class of new drugs called tyrosine kinase inhibitors
- The patients tend to be younger and non-smokers, which means they usually have fewer dangerous mutations
- Newer drugs are being developed as part of recent developments in targeted cancer therapeutics
Targeted therapy involves using drugs that are designed to attack specific molecules that enable cancer to grow. Unlike chemotherapy, these drugs do not indiscriminately kill both cancer cells and healthy cells.
Further, the treatment approach is also different from immunotherapy. Drugs in the latter category stimulate or enhance the body’s natural immune system to effectively target cancer cells. Both are alternatives to traditional chemotherapy.
The Nexus Between Mutated Genes and Metabolite Proteins
The ALK gene is primarily active during the embryonic stage, regulating cell growth. In healthy adults, it is usually switched off (dormant), or expressed at very low levels. Cancer begins when ALK mutates and remains constantly in the ‘on’ state, usually due to fusing with another gene.
When a hyperactive ALK protein is created through mutation in the lungs, it triggers continuous cell growth, setting the stage for the growth of tumors. When genes like ALK are switched on, the signals tell the body’s cells to create specific proteins and enzymes.
The Harvard team studied human lung cancer cells in lab mice to isolate and identify the abnormal proteins that are triggered by mutated ALK genes. A screening process of different metabolic proteins found in lung cancer samples led them to an enzyme called GUK1.
After additional tests, the team discovered the role of GUK1 in cell growth. Cancer cells need energy-rich molecules for cell division and growth. And GUK1 was the metabolite enzyme helping mutated ALK to achieve this, by making energy-rich GTP molecules.
Even more interesting was the reaction when they disabled GUK1 entirely in tumor cells – it led to a palpable slowdown in cell growth. The results indicate that ALK-positive cancer cells rely heavily on this enzyme for uncontrolled growth.
GUK1 Enzyme is also Present in Other Lung Cancer Samples
Apart from ALK-positive adenocarcinomas, elevated GUK1 levels have also been noted in at least a few other subtypes of lung cancer. This includes squamous cell lung cancers, which are a particularly aggressive NSCLC sub-type strongly linked to heavy smokers.
The Harvard research study opens some exciting possibilities as well as many more intriguing questions. Perhaps most reassuring is the inference that GUK1 can be targeted to put brakes on unrestricted cell growth, at least in ALK-positive lung cancers.
Further research is needed to see the effectiveness of this approach in a therapeutic setting. To be precise, we need answers to the following questions:
- How many other lung cancer sub-types have GUK1 playing an active role?
- What exactly happens to cancer cells when GUK1 is blocked?
- Can the same approach be used against other types of lung cancers?
Lung cancers often have a nasty habit of responding well to initial treatments, before bouncing back with a vengeance. Where traditional chemo and radiation fail, targeted therapies involving proteins like GUK1 could help us make lung cancer less lethal in the future.
