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Rosalie Sears, Ph.D., is senior author of a new study published in Genes & Development. Her team at OHSU found that the cancer-driving protein MYC also helps damaged tumor cells survive treatment by repairing their DNA \u2014 a discovery that could lead to new strategies to make chemotherapy and other DNA-damaging therapies more effective. (OHSU\/Christine Torres Hicks)<\/p>\n
A protein best known for driving cancer growth also helps damaged tumor cells survive by repairing their DNA, according to a new study that could influence how some cancers are treated.<\/p>\n
Researchers at Oregon Health & Science University found that the protein MYC, which is overactive in most human cancers, plays a direct role in fixing dangerous breaks in DNA. By helping cancer cells survive chemotherapy and other treatments that damage DNA, the protein may contribute to tumor resistance and poor patient outcomes.<\/p>\n
The findings, published today<\/a> in Genes & Development, could open the door to new therapies that make cancer treatments more effective by blocking this repair process.<\/p>\n Rosalie Sears, Ph.D. (OHSU)<\/p>\n \u201cOur work shows that MYC isn\u2019t just helping cancer cells grow \u2014 it\u2019s also helping them survive some of the very treatments designed to kill them,\u201d said senior author Rosalie Sears, Ph.D., Krista L. Lake Chair in Cancer Research and co-director of the OHSU Brenden-Colson Center for Pancreatic Care<\/a>.<\/p>\n Gabriel Cohn, Ph.D., is first author of the study. Now a postdoctoral researcher at the University of W\u00fcrzburg, he conducted the research as a student in Sears\u2019 lab at OHSU.<\/p>\n Gabriel Cohn, Ph.D. (Courtesy)<\/p>\n \u201cThese findings are particularly relevant for aggressive cancers like pancreatic cancer, where MYC activity is often very high,\u201d he said. \u201cTumor cells in these cancers experience significant DNA damage and replication stress, yet they continue to survive and grow. Our work suggests that MYC helps these cells cope with that stress by actively promoting DNA repair.\u201d<\/p>\n MYC is one of the most-studied cancer-related proteins because it is overactive in most human cancers. For decades, scientists have known that MYC acts inside the cell\u2019s nucleus to turn genes on, revving up growth and metabolism.<\/p>\n But the new study reveals an unexpected role: When DNA is damaged \u2014 whether from the stresses of rapid growth or from chemotherapy \u2014 a modified form of MYC moves directly to the damaged DNA and helps recruit repair machinery.<\/p>\n \u201cThis is a nontraditional, or non-canonical, role for MYC,\u201d Sears said. \u201cInstead of controlling gene activity, it\u2019s physically going to sites of DNA damage and helping bring in repair proteins.\u201d<\/p>\n That ability allows cancer cells to fix DNA breaks and survive conditions that would otherwise kill them.<\/p>\n DNA damage<\/p>\n While DNA repair is normally a healthy process, it becomes a problem in cancer treatment. Many standard therapies, including chemotherapy and radiation, work by damaging DNA so severely that cancer cells can\u2019t survive.<\/p>\n If MYC helps cancer cells repair that damage, treatments can become less effective.<\/p>\n \u201cCancer therapies often depend on overwhelming tumor cells with DNA damage,\u201d Sears said. \u201cIf a cancer cell is very good at fixing that damage, it can survive treatment and keep growing.\u201d<\/p>\n The study showed that cells with an active, modified form of MYC were better at repairing DNA and more likely to survive under stressful conditions, including exposure to DNA-damaging agents.<\/p>\n The effect was especially evident in pancreatic cancer, one of the deadliest cancers. Using patient-derived pancreatic cancer cells and tumor data, the researchers found that tumors with high MYC activity also showed signs of increased DNA repair and were linked to worse patient outcomes.<\/p>\n The findings help explain why some tumors resist chemotherapy and radiation, both of which work by overwhelming cancer cells with DNA damage. By rapidly repairing that damage, MYC-driven tumors may endure treatment that would otherwise kill them.<\/p>\n \u201cIn pancreatic cancer, MYC appears to help tumors tolerate extreme stress,\u201d Sears said. \u201cThat stress comes from rapid growth, from poor blood supply, and from chemotherapy.\u201d<\/p>\n Precise target<\/p>\n Importantly, the study supports ongoing efforts at OHSU to target MYC in people with cancer \u2014 something long thought to be impossible.<\/p>\n MYC has often been described as \u201cundruggable,\u201d meaning its structure is not amenable to drug binding, and it is hard to block safely without harming normal cells. But Sears and her colleagues believe this newly discovered repair-related function could offer a more precise target.<\/p>\n \u201cMYC is one of the two most important oncogenes in all of human cancer,\u201d Sears said. \u201cIf we can interfere with MYC\u2019s role in DNA repair \u2014 without shutting down everything MYC does in healthy cells \u2014 we may be able to make cancer cells more vulnerable to treatment.\u201d<\/p>\n At OHSU, researchers are already studying a first-in-class MYC inhibitor in a \u201cwindow of opportunity\u201d trial, a short-term study where people with advanced pancreatic cancer are biopsied before and after taking a drug called OMO-103<\/a> with the goal of understanding how blocking MYC affects tumors in real patients.<\/p>\n In our interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research, Sears reports consulting services for Revolution Medicine and Larkspur Bioscience. This potential conflict of interest has been reviewed and managed by OHSU. Review\u00a0details of OHSU’s conflict of interest program<\/a>\u00a0to find out more about how we manage these business relationships.<\/p>\n This work was supported by the National Cancer Institute, of the National Institutes of Health, under award numbers NCI U01CA294548, U01CA224012, U01CA278923, R01CA186241, R01CA287672, R21CA263996, the\u00a0Department of Defense, award\u00a0PA210068, the Brenden-Colson Center for Pancreatic Care, the Krista L. Lake Endowed Chair and the Knight Cancer Institute stipend award. The authors acknowledge expert technical assistance by the OHSU Advanced Light Microscopy Core and the Flow Cytometry Shared Resource supported by the OHSU Knight Cancer Institute.<\/p>\n","protected":false},"excerpt":{"rendered":"Rosalie Sears, Ph.D., is senior author of a new study published in Genes & Development. 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