Sidebar: What is a Pathway?

When I was a kid, there was a popular board game called “Mousetrap.” It had all of these odd assorted plastic pieces — a bathtub, a bucket, a seesaw, a boot on a swinging pole, etc. Players built a machine that could trap each other’s game pieces when triggered, through a roundabout series of connected actions from one piece to the next until the trap was tripped. The idea was inspired by the drawings of Rube Goldberg, who imagined all kinds of unlikely machines that used funny parts in cumbersome and intricate arrangements to perform often very mundane actions, like toasting a piece of bread or feeding a cat.

An original Rube Goldberg machine

Biological pathways are similar in many ways to Rube Goldberg machines. A pathway is a cascading series of actions by molecules in a cell (often proteins of various kinds) that ultimately produces one or more results, like turning genes on and off, sending signals within or outside the cell, changing the cell’s structure, or manufacturing other molecules. Often these pathways have lots of steps involving many molecular parts, and sometimes the same parts perform different functions in unrelated pathways (because Nature likes to reuse things whenever possible) — kind of like using a bathtub or seesaw as part of a mousetrap. Pathways also cross — so one pathway can trigger another in the course of its activities (imagine a mousetrap that also sets off an alarm bell when it’s tripped).

What a pathway looks like (from 10.1371/journal.pcbi.0030036)

Because pathways have a lot of complex moving parts, and there is often reuse of these parts, there are ample opportunities for failures in these pathways. If a crucial piece is malformed, or overabundant or absent, the pathway might not activate at all — or in other cases, might get stuck in the “on” mode, doing the same thing over and over again without stopping when it should. Most of these parts are proteins produced from gene instructions, so the errors that cause these pathways to break often originate from broken genes (DNA).

These broken pathways are often present in disease — not just cancer, but other types of disease as well — but they are important hallmarks in almost all cancers. Which pathways are broken, and which specific moving parts within them are at fault, vary from cancer to cancer and even within cancers. So finding out what’s going on with these pathways is crucial to understanding the disease and how to treat it. These pathways are the targets of many modern therapy trials. Genetic testing also can help ascertain which types of broken pathways are present in your cancer specifically and can direct you to appropriate therapy.

Because pathways have a lot of moving parts, it’s sometimes possible to “fix” the pathway by targeting something other than what is actually broken — for instance, if the pathway is jammed “on” by a broken signaling protein, the pathway can be shut down by jamming something else further downstream. And since there is some reuse of parts, and also some crossover in terms of which pathways are broken among different cancer types, some new drugs can work for more than one type of cancer because they fix common pathway errors found in those cancers, even if the specific causative broken parts are different. This theme is also the reasoning behind a new kind of cancer genetic test from Foundation Medicine, which looks in great detail at the DNA from your tumor to see what pathways are broken — which could lead your doctors to use a therapy for you that never would have seemed like an option with this information (for instance, using a leukemia drug to treat esophageal cancer, because it just so happens to share similarities in a particular patient’s case).

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