MSK Researchers Discover How Cancer Cells Change Identity To Escape Therapies

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MSK physician-scientist Charles Sawyers and SKI computational biologist Dana Pe’er

MSK researchers Charles Sawyers and Dana Pe’er discovered that inflammatory signaling pathways play a key role when prostate cancer cells convert to a different cell type — a transformation known as lineage plasticity.

Cancer cells are adept at developing ways to evade treatments. For example, prostate cancer becomes resistant to hormone therapy by changing a protein called the androgen receptor (AR), which plays a key role in determining cellular identity. When this change occurs, the treatment can no longer get a foothold. Researchers have designed ever more potent AR-targeting drugs to overcome this hurdle, but some prostate cancers still escape — and it’s not been clear why.

In the past few years, Memorial Sloan Kettering Cancer Center (MSK) researchers found a startling reason: Some prostate tumor cells completely change their identity to survive. This transformation, known as lineage plasticity, allows cancer cells to convert to a different cell type.

The reason AR-targeted drugs work in prostate cancer is that the particular cell lineage requires the androgen receptor to survive. When prostate cancer cells transition from adenocarcinoma cells to squamous or neuroendocrine cells, the new cancer cells no longer rely on the androgen receptor protein. But how do the cells accomplish this shape-shifting trick?

Now research done in laboratory models and led by physician-scientist Charles Sawyers and Sloan Kettering Institute computational biologist Dana Pe’er has found that the cells enter the plastic state by activating inflammatory signaling pathways called JAK/STAT and FGFR. In addition, they showed that blocking these signaling pathways, if done early enough, can cause cells that were in the transition phase to revert to their original form, so they are once again sensitive to AR-targeted drugs. The findings could open the door to new clinical approaches.

This isn't a cancer cell making a minor change to alter a protein that a drug is targeting, but instead becoming a fundamentally new thing.
Dana Pe'er computational biologist

“While it’s scary to know that a tumor has the ability to once again outsmart our drugs, this finding points to a strategy for stopping or slowing the process,” says Dr. Sawyers, the Marie-Josée Kravis and Henry R. Kravis Chair in Human Oncology and Pathogenesis. “We really understand this at a much better level than we did just a few years ago.”

The findings were reported in the August 18 issue of Science.

“This is a very complex form of drug resistance,” Dr. Pe’er says. “This isn’t a cancer cell making a minor change to alter a protein that a drug is targeting, but instead becoming a fundamentally new thing. Usually when a cell develops into a specific type, that state is permanent — it no longer can change — but we are seeing cells switch their identity.”

A Novel Research Model Shows Transition Happening

Dr. Sawyers first became intrigued by the idea of cells changing type after medical oncologist Charles Rudin, Chief of the Thoracic Service, noticed similar plasticity in lung cancer cells. During treatment, the tumors transformed from adenocarcinoma to small cell lung cancer. Dr. Sawyers knew of the same phenomenon in prostate cancer and wanted to pinpoint when the conversion takes place — and what causes it.

His lab developed an experimental system to watch the process unfold. This included two important parts. One was a genetically engineered mouse model for prostate cancer. The other involved mouse prostate cancer cells put into organoids, three-dimensional structures composed of cells grouped together and spatially arranged like an organ or tissue.

“That was the first breakthrough in this research — creating the system,” Dr. Sawyers says. “It allowed us to track the changes in the cells at every step.”

The researchers first studied prostate cells in the mouse models, which develop prostate cancer in a way that’s similar to the prostate cancer that grows resistant to AR inhibitors in people.

They used a powerful technology called single-cell genomics, which enables researchers to look closely at individual cells to determine which genes are expressed, or “turned on.” (Dr. Pe’er is a world-renowned expert in this technique.) The analysis revealed that JAK/STAT and FGFR were especially active at the point when cells began transitioning to the new type.

While it's scary to know that a tumor has the ability to once again outsmart our drugs, this finding points to a strategy for stopping or slowing the process.
Charles L. Sawyers physician-scientist

This suggested JAK/STAT and FGFR might be bringing about the plasticity, but it was not clear whether the cells could transform on their own. Inflammation is part of the immune response, so it was possible immune cells around the tumor were sending signals to the cancer cells to trigger the plasticity.

The researchers were able to answer this question of causation using the organoids, which contained only mouse prostate cells — no immune cells. Single-cell analysis showed the same activation of JAK/STAT and FGFR, providing solid evidence that the inflammatory signal was causing plasticity and that this was triggered directly within the prostate cells.

“It takes about four weeks in the organoid system to see the cells start to change with your own eyes,” Dr. Sawyers says. “But with single-cell analysis, you see the molecular alterations first and then the actual changes in the cell’s morphology [shape and structure], like watching a movie unfold.”

In the organoids, the prostate cells did not complete the transition all the way to the final stage — they needed to be put back into the mouse prostate for this to happen. This suggests that signals from other cells play a crucial role as well.

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Blocking the Transition to Restore Drugs’ Effectiveness

How might this discovery help patients? In the organoid models, the researchers showed that giving JAK/STAT and FGFR inhibitors could cause the prostate cancer cells to revert to a state where they were once again dependent on androgen receptors — and responsive to AR-targeting drugs. This suggests the same approach could work in humans.

“What’s very much next on my list is to take a finding like this and see if we can get something into the clinic that’s smartly designed, based on the preclinical data,” Dr. Sawyers says.

Patients whose prostate tumors have developed resistance to hormone therapy and have high levels of JAK/STAT and FGFR signaling might receive inhibitors that stop them early in the transition phase. Dr. Sawyers says that in the short term, biopsies would be needed to stratify (or group) patients, but he hopes a blood-based biomarker can be identified that would make it possible to get the necessary information from a blood test. He sees the current finding dovetailing with prostate cancer research reported in May 2022 by MSK physician-scientist Yu Chen, also published in Science.

“They defined four different categories of resistant prostate cancer, and one of them really matches this inflammatory-signaling subset we’re describing in our research,” Dr. Sawyers says. “There’s a synergy between their story and our story that might lead to a blood-based biomarker.”

Drs. Sawyers and Pe’er praised MSK’s Marie-Josée and Henry R. Kravis Foundation for funding preclinical laboratory research on tumor ecosystems and how they affect cancer cell behavior.

“They deserve tremendous credit for believing in us so much and giving us the resources to answer these questions,” Dr. Pe’er says.

 

 
Key Takeaways
  • Prostate cancer can develop resistance to drugs targeting the androgen receptor (AR).
  • Researchers discovered some prostate cancer cells convert to a completely different cell type.
  • The new type doesn’t rely on the AR receptor, which is why the drugs stop working.
  • The cancer cells enter the plastic state by activating the inflammatory pathway.
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This research by Dr. Sawyers and Pe’er was supported in part by the Howard Hughes Medical Institute; National Institutes of Health grants CA193837, CA092629, CA224079, CA155169, CA008748, and CA209975; Starr Cancer Consortium (I12–0007); the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center; and the Marie-Josée and Henry R. Kravis Foundation.

Competing Interests: Dr. Sawyers is on the Board of Directors of Novartis, is a co-founder of ORIC Pharmaceuticals, and is a co-inventor of the prostate cancer drugs enzalutamide and apalutamide, covered by U.S. patents 7,709,517, 8,183,274, 9,126,941, 8,445,507, 8,802,689, and 9,388,159 filed by the University of California. He also is on the Scientific Advisory Boards of the following biotechnology companies: Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ Therapeutics, Petra Pharma, and PMV Pharma, and is a co-founder of Seragon Pharmaceuticals, purchased by Genentech/Roche in 2014. Dr. Pe’er is on the Scientific Advisory Board of Insitro.