At the University of Kentucky, scientists have identified a molecular mechanism behind the spread of melanoma. Better, the scientists say that interfering with the mechanism could prevent nonmetastatic melanoma from becoming highly aggressive metastatic melanoma. Better still, the scientists point out that the mechanism could be inhibited by drugs that already exist. These drugs, which are called Abl and Arg inhibitors, have been used for decades against leukemia, and they have the added benefit of causing few side effects.
In the context of melanoma, Abl and Arg inhibitors would be useful because they would hinder the synthesis of cathepsins, enzymes that degrade proteins and are highly expressed in cancer cells. Cathepsins “chew up” the fibrous matrix around tumors, which allows bits of the tumors to get into the bloodstream and lymphatic system, facilitating melanoma invasion of distant organ sites, such as the lung, liver, brain, and bone.
A recent study conducted by the University of Kentucky scientists showed that Abl and Arg can raise cathepsin levels by increasing the activity of transcription factors, which bind to the regulatory part of genes and induce their expression. The transcription factors prompted by Abl and Arg happen to upregulate numerous proteins in involved in metastasis.
Details of this work appeared February 20 in the journal Science Signaling, in an article entitled “Abl and Arg Mediate Cysteine Cathepsin Secretion to Facilitate Melanoma Invasion and Metastasis.” The article describes the signaling pathways that lead to so much cathepsin being produced in cancer cells that the enzyme ends up being released into the environment between cells.
“We found that the nonreceptor tyrosine kinases Abl and Arg (Abl/Arg) promoted the secretion of cathepsin B and cathepsin L by activating transcription factors (namely, Ets1, Sp1, and NF-κB/p65) that have key roles in the epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance,” the article’s authors wrote. “As an indication of clinical relevance, the abundance of mRNAs encoding Abl/Arg, Sp1, Ets1, and cathepsins was positively correlated in primary melanomas, and Abl/Arg-driven invasion in culture and metastasis in vivo required cathepsin secretion.”
The researchers also reported that ABL kinases inhibitors already approved by the FDA for treating leukemia also prevented metastasis induced by secreted cathepsins in animal models of metastatic melanoma. The researchers added that the inhibitors might also be effective against other aggressive cancers harboring activated Abl kinases.
“These data have important therapeutic implications, as drugs that inhibit ABL kinases have been used for decades to treat leukemia with few side effects,” said Rakshamani Tripathi, Ph.D., postdoctoral scholar in the University of Kentucky’s department of pharmacology and nutritional sciences and lead author on the study. “Repurposing these drugs may represent a new strategy for targeting cathepsins and may be an effective approach for treating metastatic melanoma patients.”
The number of new cases of melanoma, as well as melanoma death rates, have increased steadily for the past 30 years in the U.S. Metastasis to distant organ sites is the major cause of melanoma-related deaths. Despite new advances in metastatic melanoma treatment, the 5-year survival rate is only 15% to 20%.