New research in the journal Nature Communications on how cancer mutations influence a certain type of receptor on the cell membrane opens the way for the development of tailored drugs for certain cancers, such as rectal cancer and lung cancer.
"Class F receptor dysfunction can be linked to different forms of cancer," says the study leader. "We can now describe in molecular detail how the receptors are activated and try to find drugs that stop this activation to prevent tumor growth."
The receptors on the cell membrane are activated by hormones or messenger molecules, which trigger a cascade of processes within. G protein-coupled receptors are one of the largest protein families in the body and are already an established drug target for a whole range of diseases. An important subgroup of G protein-coupled receptors are the so-called Class F receptors, but to date they have not constituted a therapeutic target to any great extent.
In this present study, the researchers used newly developed methods to compare the mutation frequency of Class F receptors in tumors with the normal population. In linking cancer mutations to receptor function in this way, they claim to have opened up new opportunities for mechanism-based drug discovery. The study describes for the first time how regions of the Class F receptor act as a kind of switch for receptor activation, and how mutations in the receptor molecules can drive tumor development.
Authors identify a conserved basic amino acid in TM6 in Class F receptors that acts as a molecular switch to mediate receptor activation. Across all tested Class F receptors (FZD4,5,6,7, SMO), mutation of the molecular switch confers an increased potency of agonists by stabilizing an active conformation as assessed by engineered mini G proteins as conformational sensors. Disruption of the switch abrogates the functional interaction between FZDs and the phosphoprotein Dishevelled, supporting conformational selection as a prerequisite for functional selectivity.
According the senior author, there are indications that other diseases, such as fibrosis, can also be linked to Class F receptor dysfunction. The researchers are currently working with the Swedish national research facility SciLifeLab to develop their ideas and explore potential new drugs.
"Drugs targeting receptors in this group have been unspecific," the senior author says. "We hope that it will now be possible to develop more effective drugs that can target individual receptors, drugs for cancers such as rectal, cervical and lung cancer."
How mutation in cell receptors affect cancer growth
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