Link established between a molecular driver of melanoma and novel therapeutic agent

September 7, 2017, The Wistar Institute

Results of a study by The Wistar Institute have described a correlation between a key melanoma signaling pathway and a novel class of drugs being tested in the clinic as adjuvant therapy for advanced melanoma, providing useful information for a more effective use of this type of treatment. The study was published online in Cancer Research.

Melanoma is the deadliest form of skin cancer. In recent years, there has been a large effort for the development of targeted therapies that inhibit specific signaling pathways required for proliferation of tumor and melanoma progression. However, the effectiveness of this therapeutic approach is only temporary, as tumors eventually become resistant, emphasizing the need for other therapeutic options.

Autophagy is a metabolic process that provides resources for the synthesis of new macromolecules through the degradation of cellular constituents. It allows cancer cells to survive under stressful conditions in the tumor microenvironment. Because it also affects the response to melanoma targeted therapy, several studies are investigating the potential of inhibiting as a strategy to improve sensitivity to targeted therapy, with some autophagy inhibitors currently moving into clinical trials. This latest Wistar study provides important, new information on the interplay of autophagy with the Wnt signaling , a key regulator of melanoma progression and metastasis.

"We have already shown that Wnt5A, a component of the Wnt pathway, plays critical roles in melanoma progression," said Ashani Weeraratna, Ph.D., Ira Brind Associate Professor and co-program leader of the Immunology, Microenvironment and Metastasis Program at Wistar and corresponding author of the paper. "Our new study indicates a link between the Wnt pathway and autophagy, whereby Wnt is a key player in the response to autophagy inhibitors and likely affects the efficacy of this class of drugs."

Weeraratna and colleagues assessed the interplay between Wnt5A, a key molecule in the Wnt pathway, and autophagy by combining expression studies in human melanoma biopsies with functional analysesin cell lines and mouse models. In particular, they found a direct correlation between expression levels of Wnt5A, which also correlate with melanoma progression, and activation of autophagy. They then observed a reciprocal regulation of autophagy and Wnt signaling. This prompted them to test in vitro and in vivo how the response of melanoma to an autophagy inhibitor is affected by Wnt signaling activation.

They observed that cells with high levels of Wnt5A and autophagy activation are less sensitive and require higher concentrations of the inhibitor. They also found that the pharmacological modulation of another molecule of the Wnt pathway, β-catenin, significantly improves the response of aggressive melanoma cells to autophagy inhibition, lowering the dose required to eradicate these cells.

"By dissecting the crosstalk between the autophagy pathway and the Wnt pathway, we discovered that signaling changes that occur within the tumor may affect the response to autophagy inhibitors," said Abibatou Ndoye, a graduate student in the Weeraratna lab and first author of the study. "Our observations will be helpful to determine which patients will be more responsive to this therapeutic strategy and how we can target the pathways that affect the response, in order to overcome resistance."

Through the new link established between autophagy and Wnt, the study also proposes a novel role of autophagy in melanoma invasion and suggests that autophagy inhibitors may be useful in treatment beyond their ability to render the cells more sensitive to targeted therapy.

Explore further: Study suggests that autophagy inhibitors could improve efficacy of chemotherapies

Related Stories

Study suggests that autophagy inhibitors could improve efficacy of chemotherapies

October 24, 2016
Chemotherapies treat cancer by killing tumor cells, but certain types of chemotherapy can also drive an immune system response to target and destroy the remaining tumor cells.

Blocking autophagy with malaria drug may help overcome resistance to melanoma BRAF drugs

February 24, 2014
Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.

Anti-aging gene identified as a promising therapeutic target for older melanoma patients

February 23, 2017
Scientists at The Wistar Institute have shown that an anti-diabetic drug can inhibit the growth of melanoma in older patients by activating an anti-aging gene that in turn inhibits a protein involved in metastatic progression ...

Study shows biomarkers can predict which ER-positive breast cancer patients respond best to first-line therapy

June 27, 2017
Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been an inability to predict who will respond to standard therapies and adverse events leading to therapy discontinuation. A study at The ...

Researchers identify how 'phenotype switching' can make melanoma become metastatic and resistant to drugs

October 18, 2013
(Medical Xpress)—One of the challenges of understanding cancer is trying to determine the mechanisms that drive metastasis, or the process by which tumor cells are able to spread throughout the body. In order to investigate ...

Scientists discover a specific molecular biomarker for malignant melanoma

September 7, 2016
Melanoma is one of the types of cancer that poses the greatest challenge to researchers because it manifests in many ways, it contains a large number of mutations and displays high metastatic capacity. To date, clinicians ...

Recommended for you

Research team discovers drug compound that stops cancer cells from spreading

June 22, 2018
Fighting cancer means killing cancer cells. However, oncologists know that it's also important to halt the movement of cancer cells before they spread throughout the body. New research, published today in the journal Nature ...

Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant

June 21, 2018
A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.

Existing treatment could be used for common 'untreatable' form of lung cancer

June 21, 2018
A cancer treatment already approved for use in certain types of cancer has been found to block cell growth in a common form of lung cancer for which there is currently no specific treatment available.

Novel therapy makes oxidative stress deadly to cancer

June 21, 2018
Oxidative stress can help tumors thrive, but one way novel cancer treatments work is by pushing levels to the point where it instead helps them die, scientists report.

Higher body fat linked to lower breast cancer risk in younger women

June 21, 2018
While obesity has been shown to increase breast cancer risk in postmenopausal women, a large-scale study co-led by a University of North Carolina Lineberger Comprehensive Cancer Center researcher found the opposite is true ...

Researchers uncover new target to stop cancer growth

June 21, 2018
Researchers at the University of Wisconsin-Madison have discovered that a protein called Munc13-4 helps cancer cells secrete large numbers of exosomes—tiny, membrane-bound packages containing proteins and RNAs that stimulate ...

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.