Melanoma Cells Rewire Their Signaling Pathways to Resist Drug Treatment
PHILADELPHIA — (Sept. 27, 2017) — Almost all patients with metastatic melanoma treated with combination therapies eventually relapse. New research led by The Wistar Institute and the University of Pennsylvania characterized the compensatory alterations that occur in melanoma signaling pathways allowing melanoma cells to escape therapy. The study was published in the journal Nature.
“Our findings provide a possible flanking strategy to counteract the ability of melanoma cells to re-wire their signaling networks,” said co-corresponding author Meenhard Herlyn, D.V.M., D.Sc., Caspar Wistar Professor in Melanoma Research and director of The Wistar Institute Melanoma Research Center. Herlyn collaborated in this research with Wei Guo, Ph.D., professor of Biology at the School of Arts & Sciences of the University of Pennsylvania, and Xiaowei Xu, M.D., Ph.D., professor of Pathology and Laboratory Medicine and Dermatology at the Perelman School of Medicine of the University of Pennsylvania.
Around half of all melanomas are attributable to a mutation in a gene called BRAF. The mutation causes the BRAF protein to become overactive, leading to increased cellular growth—a hallmark of cancer. Drugs have been developed to inhibit BRAF but these therapies have been limited by the occurrence of resistance. To bolster the effects of the BRAF inhibitors, a new class of drugs was developed to block MEK, an enzyme that acts downstream of BRAF.
Pairing BRAF inhibition with MEK inhibition has given patients with advanced melanoma one of their best treatment options yet, but unfortunately the therapeutic effect is only temporary and almost all patients on the regimen eventually relapse. While the combination therapies block off the principal pathway that melanoma cells use to fuel their growth, the cells come to bypass this blockade and, like vehicles on a detour route, make use of additional pathways to continue growing and spreading.
To uncover how this resistance occurs, Guo, Xu, Herlyn and colleagues examined both cell lines and tumor biopsies from melanoma patients before and after either BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy. As other groups had previously shown, they found that treatment with BRAF inhibitors alone seemed to reactivate ERK, a protein that is downstream of BRAF in the pathway.
However, in 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.
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 BRAF and MEK inhibition. 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, the researchers found.
“It seems it is only when the ERK pathway is inhibited that PAK becomes ‘awake,’” Guo said. “Then you can apply the PAK inhibitor and see an effect.” This explains why previous attempts at blocking PAK as an anti-melanoma strategy was not effective to stop melanoma progression.
“When cancer gets smart, we have to act even smarter,” Herlyn added.
This work was supported by National Institutes of Health grants GM085146, CA193417, CA174523, CA114046, CA25874, CA114046 and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Co-authors of this study from The Wistar Institute include co-first author Gao Zhang, Sergio Randell, Norah Sadek, Lawrence W. Wu, Clemens Krepler, Katrin Sproesser, Min Xiao, and Jianglan Liu. Other co-authors include Bin Wu, Yueyao Zhu, Wenqun Zhong, Wei Zhang, Gang Chen, Jingwen Zeng, Claire D. Song, Xiaoming Liu, Wei Xu, Jephrey Y. Liu, Lynn M. Schuchter, Jeffrey Field, Giorgos C. Karakousis, and Ravi K. Amaravadi from the University of Pennsylvania; Dennie T. Frederick, Benchun Miao, Ryan J. Sullivan, Keith T. Flaherty and Genevieve M. Boland from Massachusetts General Hospital; Yi Hu from Drexel University; Chaoran Cheng and Jie Zhang from New Jersey Institute of Technology; Yiling Lu and Gordon Mills from The University of Texas MD Anderson Cancer Center; Yusheng Cong from Hangzhou Normal University School of Medicine, China; Jonathan Chernoff from Fox Chase Cancer Center; and Jun Guo from Peking University, China.
About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
About the University of Pennsylvania
The University of Pennsylvania is an Ivy League institution founded in 1740 by Benjamin Franklin. Its 12 undergraduate, graduate and professional schools are located in Philadelphia on an urban campus with more than 20,000 students from throughout the world. Ranked consistently among the top universities in the nation, Penn has a longstanding reputation for excellence.