Susanna Greer, Chief Scientific Officer at the V Foundation for Cancer Research, published the following newsletter on LinkedIn:

”This week’s Cool Cancer Find focuses on non-small cell lung cancer (NSCLC); the most common type of lung cancer globally, representing about 80-85% of cases. Survival rates vary for NSCLC, but are generally low, with an overall 5-year survival rate around 25%. Tough statistics and we need to do better. And, while targeted therapies show promise in treating NSCLC, drug resistance remains a significant challenge, limiting long-term effectiveness.

Which brings us to the promising findings I am excited to share this week from the V Foundation grantee Timothy Burns from the University of Pittsburgh School of Medicine.

This research unravels a significant mystery in treating NSCLC where we’ve known a major problem is drug resistance. Let’s pause for a moment to think about why these findings are so important.

First, drug resistance means that the targeted therapies designed to attack the very specific molecular targets within cancer cells have stop working effectively. Meaning what? NSCLC patients need new drugs, and we need research to understand the molecular pathways to get there.

Why is drug resistance such a challenge in NSCLC? Great question! NSCLC is not a single disease, but rather a collection of distinct tumors caused by different mutations. This understanding has led to progress in treating NSCLC by targeting specific mutations driving the different types of NSCLC, ie, all the tumor types. But, for a subset of NSCLC patients, resistance to these drugs inevitably develops, leaving many patients without effective treatment options.

Findings from the Burns’ lab suggest a new strategy to tackle drug resistance. The paper is focused on understanding the protein TWIST1 and the MET pathway, and how both contribute to resistance in NSCLC.

First, let’s talk about MET. Imagine every cell in your body is a busy city, and proteins within each cell are workers with different jobs keeping everything running smoothly. Now, inside these cellular cities, there’s a pathway called the MET pathway, and it’s an expressway for cell communication.

MET acts a receiver for critical cellular messages. Think of MET as a cell’s antenna. When a specific signal comes along, it’s like a message being sent into the city. In this case, inside our cell, through the MET pathway.

When the MET antenna gets triggered, a relay race starts, with each step passing information as baton. MET triggers all sorts of responses cells, like telling cells to grow, divide, or even migrate to other parts of the body.

And here’s where things get interesting: sometimes, this MET pathway goes haywire. Imagine if a bunch of pranksters sent fake messages to the MET antennae, causing it to constantly start the ‘relay race’, even when it’s not supposed to. This can lead to uncontrolled cell growth, invasion into neighboring tissues, and ultimately, the formation of tumors.

This happens ALL the time in NSCLC, so the V Foundation grantee Timothy Burns is studying the MET pathway closely, trying to understand how it goes wrong and how to stop the relay race when it’s out of control. In essence: the Burns’ lab is working to develop drugs that can block the MET antennae, essentially cutting off the communication lines that fuel tumor growth.

So, what about TWIST? Well, what the Burns’ lab has shown is that when cancer cells become resistant to therapies targeting the MET pathway, it’s like the cells have found exit ramps off the MET communication expressway. They show the TWIST1 protein seems to be one of the worst troublemakers, TWIST is overexpressed in a lot of NSCLCs, especially those with aggressive behaviors.

What does their research mean, exactly? Well, TWIST1 seems to sneak into the control room of the MET pathway. It tampers with the switches and dials, disrupting the normal signals that keep the pathway in check.

But TWIST1 doesn’t stop there. This research shows that TWIST influences other aspects of NSCLC’s behavior, making it more resistant to targeted therapies. It’s like giving NSCLC a shield against the drugs that are supposed to stop it in its tracks.

So, I love this paper for two reasons: first, this research shows the importance of TWIST1 in causing resistance to targeted therapies in NSCLC, particularly those targeting the MET gene. And second, we now know that by targeting TWIST1 alongside existing drugs, it may be possible to overcome drug resistance and improve treatment outcomes for patients with NSCLC.

Follow the Burns lab at Hematology/Oncology Department of Medicine at University of Pittsburgh and read their paper.”

Source: Susanna Greer/LinkedIn

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