How melanoma evades targeted therapies

"The findings give us new clues about how we might combat resistance to this targeted melanoma therapy," said Andrew Aplin, PhD, Associate Director for Basic Research and the Program Leader for Cancer Cell Biology and Signaling (CCBS) at the Sidney Kimmel Cancer Center. The research was published November 6th inCell Reports.

About 13-30 percent of melanomas become resistant to RAF-inhibiting drugs because of a difference in how those cells produce and process the BRAF protein. The gene these patients carry is called a BRAF V600E isoform. These RAF-resistant isoform cancers produce BRAF proteins that become active complexes with another cancer-promoting protein called MEK.

第一作者迈克尔·贝多一起Aplin博士, an MD/PHD student in Dr. Aplin's lab and colleagues, showed that when they blocked this complex, or dimerization, by targeting a specific site on the BRAF isoform, they could block MEK binding and restore the potency of the RAF-inhibitor.

"The work helps explain dual hypotheses for RAF-inhibitor resistance, one which focused on MEK and the other on dimerization," said Dr. Aplin. "This work weaves the two together mechanistically. The results may also help guide the design of better combination therapies for melanoma."

"This pivotal study is part of a much larger effort within the Sidney Kimmel Cancer Center at Jefferson to advance the pace of discoveries leading to clinical translation," said Karen Knudsen, PhD, Enterprise Director of the Sidney Kimmel Cancer Center. "Dr. Aplin's findings bring critical insight into the molecular underpinnings of therapeutic resistance, and nominate new possibilities for treating advanced disease."