AACR: How do melanoma cells survive drug treatment long enough to acquire drug resistance?April 16, 2018
Cancer often picks up genetic changes that allow it to resist treatment. But this takes time. How do cancer cells undergoing drug treatment survive long enough to evolve? To answer this question, a study presented at the American Association for Cancer Research (AACR) Annual Meeting 2018 used real-time, single-cell imaging to make movies of live cancer cells responding to treatment with an anti-cancer drug. All cells stopped dividing in response to the drug, as expected. And then within 2-3 days, some cells restarted. By rewinding the tape of the cells that tolerated therapy - effectively, playing the movie in reverse - researchers examined how cells are able to evade drug action, long before they have acquired drug resistance mutations.
The study, led by Sabrina Spencer, PhD, investigator at the University of Colorado Cancer Center and assistant professor in the CU Boulder Department of Chemistry and Biochemistry, worked with melanoma cells harboring BRAF-V600E mutation. In many ways, these cells are an iconic example of cancer driven by a single, known mutation. Hyper-activation of the BRAF gene starts the cancer, and the FDA-approved BRAF-inhibitor dabrafenib stops it. That is, for 6-7 months, at which point BRAF-V600E melanoma tends to develop resistance to dabrafenib.
When melanomas hyper-activate BRAF, the gene turns on a pathway that drives proliferation, called the MAPK pathway. But hyper-activation of BRAF isn't the only way to hyper-activate proliferation. Sure enough, melanomas with the BRAF-V600E mutation that become resistant to dabrafenib can do so by reactivating Mek, a component of the MAPK pathway. (The FDA recently approved combination treatment in BRAF+ melanoma, using dabrafenib against BRAF and trametinib against MEK to delay this escape.)
But, again, melanoma needs time to acquire mutations that reactive the MAPK pathway or, for that matter, any other genetic escape route. Dabrafenib should eliminate melanoma cells before they can evolve this escape. But some cells survive.
"What we're looking at here is the immediate response of melanoma cells to BRAF inhibitor treatment, in real time, over the first few days of treatment. Not genetic changes, but the mechanisms the cell uses to evade treatment and start dividing again in a matter of a few days," Spencer says.
She watches this evasion with a new technique known as single-cell time-lapse microscopy and MATLAB-based automated cell tracking, which is, very basically, a way to keep a microscope pointed at a single cell and stitch its actions into a time-lapse movie (although Spencer suggests the actual technique may be bit more complicated than that).
Before treatment with the drug, cells were replicating on a cycle of about 14 hours. When Spencer and her PhD student Chen Yang introduced dabrafenib, the cells stopped replicating, entering a kind of suspended animation known as quiescence. Then about 72 hours later some cells woke from quiescence and started replicating again. At any point during the course of the following week, about 10 percent of these treated cells continued to actively replicate.
"In other words, ten percent of these cells had somehow tolerated this treatment that should have kept them in check," Spencer says.
Analysis showed that these cells that tolerated dabrafenib had somehow reactivated the MAPK signaling pathway within 2-3 days.
"Our next question is what could be causing this MAPK reactivation," Spencer says. One candidate was, of course, MEK. And when Spencer performed the same experiment with the combination of dabrafenib and the MEK inhibitor trametinib, no cells escaped to continue replicating.
"What we find is that dabrafenib, even at high doses, does not fully turn off the MAPK pathway, thereby enabling eventual escape from drug," Spencer says.
Again, a major question in BRAF-V600E melanoma has been how it tolerates dabrafenib long enough to acquire mutations that enable drug resistance. The answer, at least in part, may be that even within three days of treatment, melanoma cells find a way to activate MEK - not with mutations, but with a more flexible and temporary way to allow these cancer cells to signal through the MAPK pathway even in the presence of BRAF inhibition.
University of Colorado Anschutz Medical Campus
Related Cancer Articles:
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Is investment in research to develop new treatments the best approach to controlling cancer?
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.
Related Cancer Reading:
The Emperor of All Maladies: A Biography of Cancer
by Siddhartha Mukherjee (Author)
Winner of the Pulitzer Prize, and now a documentary from Ken Burns on PBS, The Emperor of All Maladies is a magnificent, profoundly humane “biography” of cancer—from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence.
Physician, researcher, and award-winning science writer, Siddhartha Mukherjee examines cancer with a cellular biologist’s precision, a historian’s perspective, and a biographer’s passion. The result is an astonishingly... View Details
AJCC Cancer Staging Manual
by Mahul B. Amin (Editor), Stephen B. Edge (Editor), Frederick L. Greene (Editor), David R. Byrd (Editor), Robert K. Brookland (Editor), Mary Kay Washington (Editor), Jeffrey E. Gershenwald (Editor), Carolyn C. Compton (Editor), Kenneth R. Hess (Editor), Daniel C. Sullivan (Editor), J. Milburn Jessup (Editor), James D. Brierley (Editor), Lauri E. Gaspar (Editor), Richard L. Schilsky (Editor), Charles M. Balch (Editor), David P. Winchester (Editor), Elliot A. Asare (Editor), Martin Madera (Editor), Donna M. Gress (Editor), Laura R. Meyer (Editor)
The AJCC Cancer Staging Manual is used by physicians and health care professionals throughout the world to facilitate the uniform description and reporting of neoplastic diseases. Proper classification and staging of cancer is essential for the physician to assign proper treatment, evaluate results of management and clinical trials, and to serve as the standard for local, regional and international reporting on cancer incidence and outcome.
Significantly expanded and developed by international disease site expert panels, the Eighth Edition AJCC Cancer Staging Manual brings together all... View Details
F*ck Cancer: A totally inappropriate self-affirming adult coloring book (Totally Inappropriate Series) (Volume 4)
by Jen Meyers (Author)
*A portion of the proceeds from this book will be donated to support research dedicated to finding a cure for cancer. Because fuck cancer.
This book is for you.
If you are fighting cancer, this is for you. If your brother, sister, mom, dad, son, daughter, relative, or friend is fighting cancer, this is for you. If you've lost someone to cancer like I have, this is for you. If cancer affects your life in any way, this is for you.
The stress of cancer can feel crushing. But perhaps this book can help you get away from it all, if only for a little... View Details
The Truth about Cancer: What You Need to Know about Cancer's History, Treatment, and Prevention
by Ty M Bollinger (Author)
Cancer touches more lives than you may think. According to the World Health Organization, one out of three women alive today, and one out of two men, will face a cancer diagnosis in their lifetime.
To Ty Bollinger, this isn’t just a statistic. It’s personal. After losing seven members of his family to cancer over the course of a decade, Ty set out on a global quest to learn as much as he possibly could about cancer treatments and the medical industry that surrounds the disease. He has written this book to share what he’s uncovered—some of which may shock you—and to give you... View Details
The Cancer-Fighting Kitchen, Second Edition: Nourishing, Big-Flavor Recipes for Cancer Treatment and Recovery
by Rebecca Katz (Author), Mat Edelson (Author)
This new and revised edition of the IACP award-winning cookbook brings the healing power of delicious, nutritious foods to those whose hearts and bodies crave a revitalizing meal, through 150 new and updated recipes.
Featuring science-based, nutrient-rich recipes that are easy to prepare and designed to give patients a much-needed boost by stimulating appetite and addressing treatment side effects including fatigue, nausea, dehydration, mouth and throat soreness, tastebud changes, and weight loss. A step-by-step guide helps patients nutritionally prepare for all phases of... View Details
The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies
by Dr. Nasha Winters ND FABNO L.Ac Dipl.OM (Author), Jess Higgins Kelley MNT (Author), Kelly Turner (Foreword)
The Optimal Terrain Ten Protocol to Reboot Cellular Health
Since the beginning of the twentieth century, cancer rates have increased exponentially―now affecting almost 50 percent of the American population. Conventional treatment continues to rely on chemotherapy, surgery, and radiation to attack cancer cells. Yet research has repeatedly shown that 95 percent of cancer cases are directly linked to diet and lifestyle. The Metabolic Approach to Cancer is the book we have been waiting for―it offers an innovative, metabolic-focused nutrition protocol that... View Details
Anticancer: A New Way of Life
by David Servan-Schreiber MD PhD (Author)
The revolutionary, New York Times bestselling guide to the powerful lifestyle changes that fight and prevent cancer—an integrative approach based on the latest scientific research
“A common-sense blueprint for healthy living.” —Chicago Tribune
“Resonating with cancer support communities and recommended nationwide.” —Los Angeles Times
“Life affirming . . . filled with practical advice.” —The Seattle Times
David Servan-Schreiber was a rising... View Details
Cancer: 50 Essential Things to Do: 2013 Edition
by Greg Anderson (Author)
The ground-breaking classic guide to surviving cancer?now completely updated!
Revised and updated for the first time since 1999, this invaluable guide to cancer recovery offers an easily accessible plan for patients and family members. Written by a cancer survivor, the book is an inspiring, action-oriented roadmap for those who choose to adopt a stance of hope and take charge of their diagnosis.
With penetrating insights that bring together more than two decades of scientifically supported research and experience, Anderson reveals a step-by-step holistic action plan... View Details
50 Days of Hope: Daily Inspiration for Your Journey through Cancer
by Lynn Eib (Author)
You’ve just heard a diagnosis that shakes your world: It's cancer. And what you long for most is the hope that everything will be okay. You are not alone. As a longtime cancer survivor, Lynn Eib knows firsthand how that feels. And as a patient advocate helping thousands facing cancer, she also knows what gives people hope. In 50 Days of Hope, Lynn shares amazing, true stories of those who have been in your shoes and discovered that when God and cancer meet, hope is never far away. Whether you’re a cancer patient or walking with a loved one on a cancer journey, you’ll find 50... View Details
Cancer: Step Outside the Box
by Ty M. Bollinger (Author)
Now in its 6th Edition (recently updated in 2014) and with over 150,000 copies sold since 2006, Cancer-Step Outside the Box is a “must-have” book that everyone should own. According to Dr. Rashid Buttar, author of The 9 Steps to Keep the Doctor Away, “Ty Bollinger's book, Cancer-Step Outside the Box, is an extraordinarily thorough and courageously well written book, brought to fruition by the dedication of a son for his departed parents. I found it difficult to put down this exceptional book once I began reading it and plan on recommending it to all my patients suffering from cancer who... View Details