Resistance Pulse

New study reveals how melanoma cells survive targeted therapies

Untreated melanoma cancer cells (left) express pERK (red), a marker of growth. Targeted anticancer drugs (right) stop most cells from growing but not all. Image: Luca Gerosa, Peter Sorger.

In recent years, targeted therapies have cemented their place as some of the most important tools in cancer treatment. These medicines are designed to block specific signals that tumor cells use to grow and spread, while at the same time leaving normal cells unharmed.

Targeted therapies can significantly extend patients’ lives, but the benefits are often only temporary. Over time, many cancers will become resistant to treatment and begin to grow again—a still-opaque phenomenon that hampers the development of true cures for cancer.

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In a study published last month in Cell Systems, researchers at Harvard Medical School have identified a new mechanism for how certain melanoma cancer cells can evade targeted therapy.

Working with cells in culture, they discovered that drug treatment leaves behind a population of “persister” melanoma cells that are able to survive and slowly divide due to sporadic, short-lived pulses of a growth signal. The signal is triggered by proteins outside of the cell and rewires growth pathways into a configuration unaffected by drugs.

The results offer a new insight into a form of reversible drug resistance that results from a cell’s environment. Understanding these environmental effects will help with the design of better therapies and drug combinations against melanoma and other cancers, the authors said.

“Preventing or overcoming drug resistance is the greatest challenge in using targeted anticancer therapies more effectively,” said senior study author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology and director of the Laboratory of Systems Pharmacology (LSP) at HMS. “Cancers become drug resistant in multiple ways, some of which involve genetic changes and others of which do not. If we can understand these resistance mechanisms, we can overcome them.”

In their study, Sorger and colleagues, led by first author Luca Gerosa, research fellow in therapeutic science at the LSP, focused on melanoma, a highly aggressive and often-lethal form of skin cancer. Around half of all melanomas involve a mutation to the gene BRAF, which locks the cellular signaling pathway MAPK into an always-on position. This leads to uncontrolled cell growth and division.

Several medicines have been approved by the U.S. Food and Drug Administration to block different components of BRAF-MAPK signaling in what is widely regarded as a triumph of targeted therapy, the authors said. These drugs can be highly effective, but resistance often arises. When this occurs, the MAPK pathway reactivates, cancer cells begin to grow and patients experience recurrent disease.

Oncogenic fireworks

To investigate how, the researchers treated BRAF-mutant melanoma cells with different targeted therapies. After drug exposure, the overall number of surviving cells appeared to be constant. But tracking individual cells revealed that some were dying and others slowly dividing, giving the appearance of a steady population.

They took snapshots of cancer cells over time and found that the vast majority responded to treatment with suppressed growth. In a small number of cells, however, MAPK signaling was still active. This was measured by looking at the activity of a key enzyme in the pathway, phosphorylated ERK.

Unexpectedly, these cells frequently clustered around each other. Using live-cell imaging to create movies of cellular activity, the team found that cells activating ERK were far from rare. Instead, over just a 16-hour period, around one in every four cells exhibited at least one roughly hour-long pulse of ERK.

Additional experiments revealed that ERK pulses appear to occur within cells that are able to divide even after drug exposure, suggesting that the pulse is linked with cell survival and drug resistance.

“We discovered that all these cells are reactivating this growth pathway, just at different times and in brief pulses,” Gerosa said. “It was similar to comparing a still picture in which a few fireworks are exploding in the sky and a movie showing that there are actually hundreds of asynchronous explosions.”

After treatment, a melanoma cell shows pulses of ERK growth signal activity (left). Eventually, it divides. A marker for cell division is shown right. Video: Luca Gerosa