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Melanoma therapy resistance mechanism identified in Sanford-Burnham study
LA JOLLA, Calif.—Recent research out of the Sanford-Burnham Medical Research Institute provides important clues about the molecular mechanisms underlying the development and progression of melanoma—the deadliest form of skin cancer—and how these mechanisms allow melanoma to resist therapy.
In a study published Feb. in the Elsevier journal Cell, the Sanford-Burnham team demonstrates how the transcription factor ATF2, which is associated with poor prognosis in melanoma, elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Led by Dr. Ze'ev Ronai, the senior author of the study, the researchers identified that the ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress.
Ronai's laboratory at Sanford-Burnham is directed toward understanding the regulation and function of the signaling pathways that play a central role in the mammalian stress response. In particular, it is focused on ubiquitin ligases and protein kinases that cooperate in the regulation of important cellular functions, including hypoxia, ER stress and the cell cycle.
"We have been working on skin cancer in its non-malignant forms for the last 20 years. In the course of these studies, we have made some important discoveries," says Ronai, who is associate director of Sanford-Burnham's NCI-designated Cancer Center. "In the last few years, we have made enormous progress in the area of melanoma to the degree that we now have specific drugs that can target forms of the tumor. Despite this progress, we now realize that we need to overcome the challenge of resistance that emerge in most cases—and there is a tremendous effort being placed on how to overcome this as we speak."
This resistance, known as oncogene addiction—which has been called the "Achilles' heel of cancer"—is defined as a condition in which disruption of one gene or protein leads to the death of the cancer cell. Many cancer research teams are working to exploit this phenomenon therapeutically by "switching off" the pathway upon which cancer cells have become dependent in an effort to destroy the cancer cell while sparing normal, healthy cells from damage.
ATF2 is a "two-faced" protein—in melanoma cells, it's oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it acts as a tumor suppressor. Ronai's team identified a molecular switch called protein kinase Cɛ (PKCɛ) that controls ATF2's dual functions. PKCɛ disables ATF2's tumor-suppressing activities, sensitizing cells to chemotherapy and enhancing ATF2's tumor-promoting activity. The team also found that high levels of PKCɛ in melanoma are associated with poor prognosis.
"PKCɛ is the culprit behind melanoma's oncogenic addiction," explains Ronai. "ATF2 is normally a 'good guy.' But when there is too much PKCɛ—as in malignant melanoma—ATF2 becomes an oncogene, promoting tumor development."
In this study, Ronai and his colleagues found that PKCɛ's malignant power is in its ability to direct ATF2's location and activity within a cell. In a normal cell, PKCɛ modifies ATF2, keeping it in the nucleus, where it turns genes on and off and helps repair damaged DNA. When the cell experiences exposure to toxicity or stress, PKCɛ backs off and ATF2 is able to move out of the nucleus and to the mitochondria, the part of the cell that generates energy and helps control cellular life and death. When it gets there, ATF2 helps to set the cell on a death course—a safeguard cells use to prevent errors that often make them cancerous.
PKCɛ levels are abnormally high in melanoma, and more PKCɛ means more ATF2 stuck in the nucleus, where it can't help the cells to die. Instead, in the nucleus, ATF2 promotes cellular survival and thus contributes to tumor development the researchers found.
Ronai's laboratory is now searching for small molecules that help release ATF2 from PKCɛ's grip, thus resuming ATF2's ability to promote cell death when needed. Since such an approach will effectively kill melanoma cells, it is expected to offer new therapeutic options for melanoma, and possibly other tumors with high PKCɛ levels.
"The development of a treatment for melanoma is moving at a tremendous pace," says Ronai. "There is great knowledge being added as we speak. I believe that by sequencing tumors from melanomas, highlighting new mutations and offering potential targets by specific immunotherapeutics, we will have a treatment for melanoma in the next two to three years. I believe we will be able to move forward in recognizing that there is no one magic drug, but a combination of drugs based on our knowledge of changes in different signaling pathways."
The study, "PKCε Promotes Oncogenic Functions of ATF2 in the Nucleus while Blocking Its Apoptotic Function at Mitochondria," was funded by the National Cancer Institute and the American Cancer Society, Illinois Division. Ronai's co-authors included Eric Lau, Sanford-Burnham; Harriet Luger, Yale University; Tal Varsano, Sanford-Burnham; KiYoung Lee, University of California, San Diego and Ajou University; Immo Scheffler, University of California, San Diego; David Rimm, Yale University; and Trey Ideker, University of California, San Diego.