uni'wissen 01-2016_ENG

“The tumor doesn’t change the drug but the dealer.” incorrectly during transcription. In its normal, non-mutated state, B-Raf has a kind of closed mouth when it is not active. Ras stimulates B-Raf to attach itself to phosphate groups, a pro- cess known as phosphorylation. B-Raf opens its mouth and is in an active state, enabling it to activate the next link in the signaling chain, MEK. The V600 mutation always has its mouth open: “The mutation puts the molecule in a state that imitates the effects of phosphorylation perfectly. Its mouth is and remains open, although B-Raf has in reality not been activated at all.” This type of mutation is present in more than 50 percent of humans suffering from melanoma skin cancer. Tumors caused by the V600E muta- tion can be treated with substances that inhibit B-Raf. However, the tumors are often resistant. “We speak of an oncogenic dependency: The tumor is addicted to the cancer-inducing signal, so to say.” Since cancer cells are often geneti- cally unstable, they can continue to develop and reactivate the Ras/B-Raf/MEK/ERK signaling path- way. In some patients, the MEK gene mutates in such a way that it can bypass B-Raf in the sign- aling chain. In others, the cancer cells succeed in increasing the quantity of Ras. Continuing to administer a B-Raf inhibitor in such a case would be fatal: “Ras then works together with the blocked B-Raf, which is still bound to the drug, to activate another variant of Raf, a cousin of B-Raf, as it were. The signaling pathway is thus activated again, often more strongly. The tumor doesn’t change the drug but the dealer.” Brummer and his research group showed in a study what happens with the mutated gene BRAFV600E leaves the cell again or is blocked by B-Raf inhibitors. It was already known previously that V600E is an oncogenic driver and therefore causes cancer. Brummer’s team confirmed this and went one step further: “You might say we fixed the blocked gas pedal. In this way, we dem- onstrated that cells do not stop growing when the mutation is bypassed but differentiate again.” This means that the cells specialize, and as a result they behave less aggressively. The prob- ability that they will leave the tumor to form me- tastases somewhere else in the body decreases. The researchers applied methods from synthetic Relay race in the cell: The proteins on the Ras/B-Raf/MEK/ERK pathway activate each other in succession, passing on the baton, so to say. This signaling chain plays an important role in numerous processes in the body, such as wound healing. Illustration: David M. Malambré – DSQ Comics + Design 10 uni wissen 01 2016 10 uni wissen 012016

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