Melanoma therapy resistance mechanism identified in Sanford-Burnham study

LA JOLLA, Calif.—Recent research out of the Sanford-BurnhamMedical Research Institute provides important clues about the molecularmechanisms underlying the development and progression of melanoma—the deadliestform 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 teamdemonstrates how the transcription factor ATF2, which is associated with poorprognosis in melanoma, elicits oncogenic activities in melanoma and tumorsuppressor activities in nonmalignant skin cancer. Led by Dr. Ze'ev Ronai, thesenior author of the study, the researchers identified that the ATF2 tumorsuppressor function is determined by its ability to localize at themitochondria, where it alters membrane permeability following genotoxic stress.

Ronai's laboratory at Sanford-Burnham is directed towardunderstanding the regulation and function of the signaling pathways that play acentral role in the mammalian stress response. In particular, it is focused onubiquitin ligases and protein kinases that cooperate in the regulation ofimportant cellular functions, including hypoxia, ER stress and the cell cycle.

"We have been working on skin cancer in its non-malignantforms for the last 20 years. In the course of these studies, we have made someimportant discoveries," says Ronai, who is associate director ofSanford-Burnham's NCI-designated Cancer Center. "In the last few years, we havemade enormous progress in the area of melanoma to the degree that we now havespecific drugs that can target forms of the tumor. Despite this progress, wenow realize that we need to overcome the challenge of resistance that emerge inmost cases—and there is a tremendous effort being placed on how to overcomethis as we speak."

This resistance, known as oncogene addiction—which has beencalled the "Achilles' heel of cancer"—is defined as a condition in whichdisruption of one gene or protein leads to the death of the cancer cell. Manycancer research teams are working to exploit this phenomenon therapeutically by"switching off" the pathway upon which cancer cells have become dependent in aneffort to destroy the cancer cell while sparing normal, healthy cells fromdamage.

ATF2 is a "two-faced" protein—in melanoma cells, it'soncogenic, or cancer-causing, while in non-malignant types of skin cancers, itacts as a tumor suppressor. Ronai's team identified a molecular switch calledprotein kinase Cɛ(PKCɛ) thatcontrols ATF2's dual functions. PKCɛ disables ATF2's tumor-suppressing activities, sensitizingcells to chemotherapy and enhancing ATF2's tumor-promoting activity. The teamalso 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 malignantmelanoma—ATF2 becomes an oncogene, promoting tumor development."

In this study, Ronai and his colleagues found that PKCɛ's malignantpower is in its ability to direct ATF2's location and activity within a cell.In a normal cell, PKCɛmodifies ATF2, keeping it in the nucleus, where it turns genes on and off andhelps repair damaged DNA. When the cell experiences exposure to toxicity orstress, PKCɛbacks 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 anddeath. When it gets there, ATF2 helps to set the cell on a death course—asafeguard cells use to prevent errors that often make them cancerous.

PKCɛ levels are abnormally high in melanoma, and more PKCɛ means more ATF2stuck in the nucleus, where it can't help the cells to die. Instead, in thenucleus, ATF2 promotes cellular survival and thus contributes to tumordevelopment the researchers found.

Ronai's laboratory is now searching for small molecules thathelp release ATF2 from PKCɛ's grip, thus resuming ATF2's ability to promote cell deathwhen needed. Since such an approach will effectively kill melanoma cells, it isexpected to offer new therapeutic options for melanoma, and possibly othertumors with high PKCɛlevels.

"The development of a treatment for melanoma is moving at atremendous pace," says Ronai. "There is great knowledge being added as wespeak. I believe that by sequencing tumors from melanomas, highlighting newmutations and offering potential targets by specific immunotherapeutics, wewill have a treatment for melanoma in the next two to three years. I believe wewill 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 differentsignaling pathways."

The study, "PKCε Promotes Oncogenic Functions of ATF2 in theNucleus while Blocking Its Apoptotic Function at Mitochondria," was funded bythe National Cancer Institute and the American Cancer Society, IllinoisDivision. Ronai's co-authors included Eric Lau, Sanford-Burnham; Harriet Luger,Yale University; Tal Varsano, Sanford-Burnham; KiYoung Lee, University ofCalifornia, San Diego and Ajou University; Immo Scheffler, University ofCalifornia, San Diego; David Rimm, Yale University; and Trey Ideker, Universityof California, San Diego.