Pharma R&D Today
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Attack of the Mutants
Posted on March 3rd, 2016 by Joanna Aldred in Chemistry
Most parents know how difficult it is to prevent children from taking up bad or unhealthy habits. Children tend to ignore their parents’ advice, convinced as they are that nothing will ever happen to them or their parents are making a fuss about nothing. One of the arguments I use to persuade my son not to smoke is to remind him that his grandmother and great grandfather both died of lung cancer so he may be genetically susceptible to this disease.
I have no idea whether my family is at risk for lung cancer and, in a true family tradition of not wanting to know the worst, I am not keen to find out. What is certain is that there are genetic variants that make some people more susceptible to lung cancer. Mutations, however, are not necessarily inherited they may occur after birth. For lung cancer, one of the most common causes of these non-inherited or somatic mutations is smoking.
Until I read the review by Cheng et al., to be honest, I had not even realised that there were 2 basic types of lung cancer: small cell and non-small cell cancer. No cancer is good to have but non-small cell cancer has the advantage of growing more slowly. Slow down the growth of cancer and you can increase life expectancy.
Treatment, as always, depends on the type of cancer involved. Cheng et al., look at the treatment being developed for cancers caused by a genetic mutation of the epidermal growth factor receptor (EGFR). As it name suggests, this mutation encourages the receptor on the cell surface to be overactive. This is a somatic mutation (although not one directly caused by smoking) which means that anyone can acquire it. Surprisingly, EGFR mutations account for 10-30% of non-small cell lung cancer so treatment for this could potentially help 100-200 thousand people a year.
Drugs are being developed which work on enzymes (kinases) which will slow down or inhibit the activity of EGFR. The first generation drugs were based on the tyrosine kinase inhibitors, gefitinib and erlotinib. After a while the drugs no longer work as patients develop resistance, with ~60% driven by T790M mutation. A further development tried to reduce the abnormal activity of EGFR while allowing normal activity (WT EGFR) but it is complex to get the balance of activity correct: stopping all EGFR activity can have uncomfortable side effects for the patient.
The newest drugs being developed (the third generation) are aiming to have no effect on the WT EGFR but only suppress abnormal activity. This research is based on two chemical techniques that will be familiar for many from high school chemistry: crystal structure and kinetics. It sounds very simple: find the right spot in the structure of mutant EGFR and attach an extra molecule to make tumors sensitive to the drug. Understanding the kinetics means that you can design drugs that will selectively react with mutant EGFR while minimizing reactivity with other proteins in the cells to minimize uncomfortable side effects.
The third generation of drugs are showing promising results and one has already been cleared for patient use under certain conditions. Unfortunately, resistance over time is building up for these drugs as with the first generation and research is needed into how this resistance is built up.
Hopefully, these developments will eventually lead to improved treatment for non-small cell lung cancer but, as ever, prevention is the best cure and avoiding carcinogens must always be the best advice. Has my son listened to my warnings? Going by the smell of smoke in his clothes I somewhat doubt it. I just hope that I never have to say “I did warn you.”
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