The study highlights the ability of cells to resist drug treatment through a non-genetic cell state transition by changing their gene expression patterns and signaling pathways. A study in collaboration with the California Institute of Technology showed on December 12, 2017, that skin cancer cells could be chemically altered to change gene expression patterns and intracellular pathways. Targeted therapies have much more potential for treatment of cancer as compared to chemotherapy due to their ability of directly targeting cancerous cells without affecting healthy cells. In many types of cancers including melanoma, cells have shown their ability to develop resistance against newer targeted inhibitors. Targeted cancer therapy is highly driven by increasing incidence of lung cancer, colorectal cancer, and gastrointestinal cancer, among others, as per targeted cancer therapies market report, published by Coherent Market Insights.
The UCLA-Caltech team conducted genome-wide expression and flow cytometry analyses on human melanoma cells that had a mutated form of BRAF, which is a target for drug inhibitors. They employed mathematical modeling of the dynamic process through which the melanoma cells developed resistance to targeted agents. They also conducted functional proteomics analysis of single melanoma cells, using a microfluidic single-cell barcode lab on a chip to determine variation of cellular responses with BRAF inhibitors.
The results further demonstrate that by blocking the pathways that allow cancer cells to resist molecular targeted therapies, the cells could be held in a drug-sensitive state so that therapy can more effectively inhibit growth. Through identifying and tracing the exact inhibitors that affect the steps in these pathways, new combinations of therapies could be developed that inhibit cancer cell transitions and improve the durability of therapies that target BRAF. However, more research is needed to determine the exact molecular pathways that trigger adaptive resistance.
The research was published in National Academy of Sciences Journal and it was supported by the National Institutes of Health, the Dr. Robert Vigen Memorial Fund, the Garcia-Corsini Family Fund, the Ressler Family Fund, the Grimaldi Family Fund, the Jean Perkins Foundation and the Phelps Family Foundation.