Potential new treatment identified for drug-resistant skin cancer

February 6, 2018 by Krista Conger, Stanford University Medical Center
Potential new treatment identified for drug-resistant skin cancer
The new research shows how some basal cell carcinomas sidestep drug treatment by importing a protein into their nuclei. Credit: CI Photos/Shutterstock

Stanford researchers have learned how basal cell carcinoma evades drug treatment without mutating. The researchers found possible drug targets that may allow for more personalized treatment of this common skin cancer.

Over half of newly diagnosed advanced or metastatic basal cell carcinomas are resistant to currently approved drug treatments. Yet many of these skin cancers harbor no known resistance-associated , leaving researchers and clinicians wondering how they manage to evade treatment.

Now, researchers at the Stanford University School of Medicine have identified a link between changes in the ' internal scaffolding and one of the last steps of the that drives their growth. This previously unknown connection allows the cells to neatly sidestep the effects of currently approved drugs without requiring them to acquire specific genetic mutations.

The researchers found that blocking this connection using an inhibitor previously used to treat inflammation significantly slowed the growth of drug-resistant basal cell carcinomas in mice. Moreover, human primary tumors grown in the lab also responded to the blockade, highlighting the therapeutic potential of this approach.

The findings suggest new ways to tackle the common skin cancer, which affects up to 30 percent of people in the United States at some point in their lives. It also may help researchers better personalize their treatments by identifying patients most likely to respond to certain drugs.

"Many of these tumors are resistant at the time of their diagnosis," said professor of dermatology Anthony Oro, MD, Ph.D. "Our findings support the idea that tumors have a 'resistance toolbox' of mechanisms from which they can choose, based on their microenviroment, that doesn't depend on genetic mutations often associated with the disease."

A paper describing the research was published online Feb. 5 in Nature Medicine. Oro is the senior author, and postdoctoral scholar Ramon Whitson, Ph.D., is the lead author.

Most common cancer in U.S.

Approximately 2 million new cases of basal cell carcinoma are diagnosed each year in the United States, making it the most common cancer in the country. Most are successfully treated with surgery, and the cancers metastasize only rarely. When they do, however, they can be deadly.

The findings show that the cancer cells sidestep drug treatment by importing a protein into the nucleus that increases the activity of a well-known molecular cascade known as the Hedgehog pathway. This pathway is critical to human development and plays a role in many types of cancer, including pancreatic, colon, lung and breast cancers, as well as to a type of brain cancer called medulloblastoma.

Anthony Oro (left) and Ramon Whitson published a study that could help explain why some basal cell carcinomas develop resistance to existing drugs. Credit: Anne Dazey

Basal cell carcinomas are uniquely dependent on the inappropriate activation of the Hedgehog pathway. This pathway functions like a Rube Goldberg machine to pass a signal sequentially from outside the cell, across the cell's membrane and into the nucleus to trigger the expression of genes important in cellular growth and development. Each step in the pathway is carried out by the activation or inhibition of specific proteins in the cell.

The cascade begins when the Hedgehog signaling protein, which is secreted by neighboring cells, binds to a receptor called Patched on the surface of cells. Patched then activates another protein on the surface of the cell called Smoothened, which translates the signal across the cell's membrane and into the interior. The final step involves the activation of a protein called GLI1 that binds to and initiates the transcription of specific genes in the nucleus. Most basal cell carcinomas have mutations in Patched or Smoothened, causing runaway activation of GLI1.

Mystery of drug resistance

In 2011, the Food and Drug Administration approved the use of a Smoothened inhibitor called vismodegib, sold under the brand name Erivedge, as a treatment for basal cell carcinoma. About half of patients with advanced basal cell carcinomas will respond to vismodegib, but about 20 percent of these responders will go on to quickly develop resistance to the drug. Oro and Whitson wanted to know why.

Previous work in Oro's lab has identified several mutations that occur in the components of the Hedgehog pathway that cause it to remain active even in the presence of vismodegib. But in about half of resistant tumors, even extensive efforts were unable to identify a responsible genetic mutation.

"We sequenced the heck out of these tumors, and many had no known mutation in genes encoding Hedgehog pathway proteins," said Oro.

When Whitson looked closely at the gene expression patterns of the cells, he noticed that GLI1—one of the last proteins of the Hedgehog pathway—remained active in the resistant cancers. This active form of GLI1 was found in a complex with another transcription factor called serum response factor. SRF is activated by another protein called megakaryoblastic leukemia 1 that is normally associated with components of the cytoskeleton, or cellular scaffolding, that helps cells maintain their shape and governs their rigidity.

Although MKL1 is normally found primarily in the cytoplasm, Whitson and Oro found elevated levels of the protein in the nucleus of resistant cells when compared with drug-susceptible tumors isolated from human patients. Furthermore, blocking the ability of MKL1 to increase GLI1 activity dramatically slowed the growth of basal cell carcinomas in mice. Additionally, Whitson found that human tumors grown in the lab responded to the MKL1 blockade by reducing GLI1 activity, suggesting this approach may benefit patients.

Because SRF and MKL1 act on one of the last steps of the Hedgehog pathway, they are able to stimulate the ' growth even in the presence of inhibitors that block steps earlier in the signaling cascade. Intriguingly, changes in a cancer cell's cytoskeleton and shape often enhance its ability to invade surrounding tissues and can lead to metastasis throughout the body.

"People have long associated changes in the extracellular matrix with tumor progression or resistance to drugs," Whitson said. "But this is the first time anyone has identified the molecular causes behind this link. Now we know that we can use the presence of nuclear MKL1 as a biomarker to identify patients who might benefit more from MKL1 or GLI1 inhibitors than from vismodegib."

"This is a common resistance mechanism in a common human tumor," Oro said, "and it doesn't require genetic mutations to turn it on. Understanding this new connection between the cytoskeleton and the Hedgehog pathway will allow us to better personalize treatments to individual patients."

Explore further: Why basal cell tumors return when drug treatment stops

More information: Ramon J Whitson et al. Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas, Nature Medicine (2018). DOI: 10.1038/nm.4476

Related Stories

Why basal cell tumors return when drug treatment stops

February 1, 2018
What happens when the most common and least threatening type of cancer gets complicated?

Skin tumors develop specific mutations to resist drug, researchers say

March 10, 2015
Among people with advanced basal cell carcinomas who see their skin cancers shrink or disappear in response to a common drug therapy, about 20 percent will relapse within months as the cancer cells become resistant to the ...

New pathway identified as a target for precision medicine against a common brain tumor

November 2, 2017
St. Jude Children's Research Hospital scientists have discovered a promising target for precision medicines to block a mechanism that drives several cancers, including about 30 percent of cases of the brain tumor called medulloblastoma. ...

Hedgehog signaling proteins keep cancer stem cells alive

January 22, 2018
Researchers from Charité - Universitätsmedizin Berlin have discovered that the survival of cancer stem cells is dependent on the Hedgehog signaling pathway. Targeting this pathway had previously shown no effect on the growth ...

Blocking a protein in a critical signaling pathway could offer a new way to combat tumors

August 10, 2016
Cancer drugs that block a cell-signaling pathway called Hedgehog have shown promise in recent years in treating patients with skin cancer, leukemia and other types of tumors. But the available treatments mostly target the ...

Scientists link two cancer-promoting pathways in esophageal cancer

March 19, 2012
Identification of a non-traditional pathway for spiriting a cancer-promoting protein into the cell nucleus points to a possible combination therapy for esophageal cancer and indicates a mechanism of resistance for new drugs ...

Recommended for you

New 'SLICE' tool can massively expand immune system's cancer-fighting repertoire

November 15, 2018
Immunotherapy can cure some cancers that until fairly recently were considered fatal. In addition to developing drugs that boost the immune system's cancer-fighting abilities, scientists are becoming expert at manipulating ...

Anti-malaria drugs have shown promise in treating cancer, and now researchers know why

November 15, 2018
Anti-malaria drugs known as chloroquines have been repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor. Now, researchers from the Abramson ...

Researchers identify a mechanism that fuels cancer cells' growth

November 14, 2018
Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose, which is key to their survival and promotes ...

A new approach to detecting cancer earlier from blood tests: study

November 14, 2018
Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy", epigenetic alterations and machine learning to develop a blood test to detect and classify ...

New antibody breakthrough to lead the fight against cancer

November 14, 2018
Scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancer's defence against the body's immune system.

Photoacoustic imaging may help doctors detect ovarian tumors earlier

November 14, 2018
Ovarian cancer claims the lives of more than 14,000 in the U.S. each year, ranking fifth among cancer deaths in women. A multidisciplinary team at Washington University in St. Louis has found an innovative way to use sound ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.