Researchers uncover cell changes behind therapy-resistant cancers, call for new clinical approaches
A UCLA study in collaboration with the California Institute of Technology (Caltech) shows that skin cancer cells could be chemically changed from within to reflexively alter gene expression patterns and intracellular pathways, which allows the cells to become resistant to targeted drugs. The findings provide a more accurate roadmap of how cellular resistance can develop non-genetically, and demonstrate that cancer cells can be chemically prodded to prevent resistance to therapy at its earliest stages. The results also suggest new avenues for effectively treating melanoma and other cancers by preventing these intracellular changes.
Over the past several years, targeted therapies against cancer have been developed as an improvement over chemotherapy. Targeted therapies, at least in theory, can narrowly impact cancerous cells without harming healthy ones. However, in many cancers including melanoma, cells have shown their ability to develop resistance against newer targeted inhibitors.
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 modelling 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 how cellular responses varied to BRAF inhibitors.
Scientists haves previously hypothesized that the source of developed resistance to targeted inhibitors resided in a cell’s ability to develop new genetic mutations that confer this resistance. This study sheds new light on that assumption, showing that cells can tolerate (resist) drug treatment through a non-genetic cell state transition by changing their gene expression patterns and signaling pathways.
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. More research is needed to determine the exact molecular pathways that trigger adaptive resistance.
The researchers are currently focused on a set of transcription factors that regulate gene expression and influence cellular processes such as immunity, inflammation, stress responses and development of immune cells. These factors play a critical role in initiating steps within cells that begin the transition to cancer resistance to therapies, and could provide valuable new targets for the development of potential treatments.
UCLA’s Drs. Wei Wei and Antoni Ribas, and Dr. James Heath at the California Institute of Technology are co-senior authors. The co-first authors are Dr. Yapeng Su at the California Institute of Technology and Drs. Wei Wei and Lidia Robert at the David Geffen School of Medicine at UCLA. Other authors are Drs. Min Xue, Jungwoo Kim, Rachel Ng and Johoon Lee at the California Institute of Technology, and Drs. Jennifer Tso, Angel Garcia-Diaz, Blanca Homet Moreno, Richard Koya, Begonya Comin-Anduix and Thomas Graeber at UCLA. Heath, Ribas, Wei, Koya, Comin-Anduix and Graeber are members of the UCLA Jonsson Comprehensive Cancer Center
The research is published online in Proceedings of the National Academy of Sciences, one of the world's most-cited and comprehensive multidisciplinary scientific journals.
The research 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.
Drs. James Heath and Antoni Ribas are affiliated with Isoplexis, which is seeking to commercialize the single-cell barcode chip technology.