Combination therapies to treat patients with metastatic melanoma that hit the market in 2014 did a good job extending people’s lives. Unfortunately, after several months of treatment, almost all patients on the new regimen eventually relapsed. Now scientists know why.
While the combination therapies block off the principal pathway that cancer cells use to fuel their growth, the cells figure out how to bypass the blockade and, like vehicles on a detour route, make use of additional pathways to continue to grow and spread.
“The tumor cells are smart,” says Wei Guo, a professor of biology at the University of Pennsylvania and co-corresponding author of the study in Nature. “Once they block this first pathway, then other pathways can get activated, leading to an even more aggressive disease.”
These parallel pathways, governed by the PAK family of enzymes, present appealing new targets for melanoma treatment.
“When cancer gets smart, we have to act even smarter.”
“Our findings provide a possible flanking strategy to counteract the ability of melanoma cells to re-wire their signaling networks,” says co-corresponding author Meenhard Herlyn, professor of melanoma research and director of the Melanoma Research Center at The Wistar Institute. “When cancer gets smart, we have to act even smarter.”
Guo and Herlyn collaborated on the work with co-corresponding authors Xiaowei Xu, a professor of pathology and laboratory medicine and dermatology at Penn’s Perelman School of Medicine.
Around half of all melanomas are attributable to a mutation in a gene called BRAF. When mutated, BRAF, an enzyme that acts in a signaling cascade known as the MAPK/ERK pathway, becomes overactive and leads to increased cellular growth, a hallmark of cancer.
Drugs developed to inhibit BRAF have been modestly successful, but some patients fail to respond entirely and those who do respond almost inevitably develop resistance.
To bolster the effects of the BRAF inhibitors, a new class of drugs was recently developed to block an enzyme that acts downstream of BRAF/MEK. Pairing the BRAF inhibitor with the MEK inhibitor gives patients with advanced melanoma one of their best treatment options to date. But like the BRAF-inhibitors, the effectiveness appears to be transient.
Several years ago, Guo and his postdoctoral researcher, Hezhe Lu, the paper’s first author, were fascinated to find that drug-resistant melanoma cells were more aggressive than their parental strains in cell-culture assay. To uncover how this resistance occurs, researchers examined both cell lines and tumor biopsies from melanoma patients before and after either BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy.
As with the case of other groups, treatment with BRAF inhibitors alone seemed to reactivate ERK, which is downstream of BRAF in the MAPK pathway.
But in many cell lines and patient samples that developed resistance to the combination therapy, the researchers observed something different happening. ERK was not reactivated. Instead, they found that a parallel pathway, governed by the enzyme PAK, was energized.
“We found not only was PAK activated in many patients, but also PAK’s downstream targets,” Guo says.
Treating cells resistant to combination therapy with a PAK inhibitor reduced their ability to grow. When the researchers did the opposite, turning on a PAK protein in a metastatic melanoma cell line, they found the cells became even more resistant to inhibitors of the MAPK pathway.
PAK proteins allow melanoma to thrive through their action on a few different pathways, both encouraging cell cycle progression and inhibiting apoptosis, a form of cell death.
Interestingly, cancer researchers attempted to block PAK as an anti-tumorigenic strategy in the past, only to find it didn’t seem to do anything to stop melanoma progression.
“It seems it is only when the ERK pathway is inhibited that PAK becomes ‘awake,'” Guo says. “Then you can apply the PAK inhibitor and see an effect.”
“Our discovery may direct new drug development efforts to target PAKs,” Xu says.
The researchers see promise in targeting PAKs as an additional tool to target melanoma tumors and are following up on some of the parallel pathways downstream of PAK to determine how they operate. They’re also pursuing research into immunotherapy approaches in melanoma treatment.
Shujing Liu of Penn and Gao Zhang of Wistar are co-lead authors of the work. Other coauthors are from the University of Pennsylvania, Wistar, Massachusetts General Hospital, Drexel University, New Jersey Institute of Technology, and the University of Texas MD Anderson. The National Institutes of Health and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation funded the work.