Scientists discover new therapeutic target for lung cancer driven by KRAS
DALLAS – July 28, 2016 – UT Southwestern Medical Center researchers have identified a new way to target lung cancer through the KRAS gene, one of the most commonly mutated genes in human cancer and one researchers have so far had difficulty targeting successfully.
Researchers studying the underlying biology of KRAS in lung cancer determined that activity resulting from the ACSL3 gene is essential for these lung cancer cells to survive, and that suppressing ACSL3 causes these lung cancer cells to die.
The findings are significant because genetic mutations of KRAS occur in about 30 percent of lung cancer cases, and they are associated with aggressive, therapy-resistant disease with a poor prognosis. Lung cancer remains the leading cause of cancer-related deaths in the U.S., according to the National Cancer Institute (NCI).
"Despite some recent advances, mutant KRAS remains a very challenging target. There is a dearth of treatment options for tumors initiated by this gene," said senior author Dr. Pier Paolo Scaglioni, Associate Professor of Internal Medicine in the Division of Hematology and Oncology, and a member of the Harold C. Simmons Comprehensive Cancer Center.
The KRAS gene (Kirsten rat sarcoma viral oncogene homolog), produces proteins called K-Ras that influence when cells divide. Mutations in K-Ras can result in normal cells dividing uncontrollably and turning cancerous.
"Mutant KRAS not only promotes the growth of tumors, but also the survival of established lung cancer. Since we have no clinically-relevant effective inhibitors of mutant KRAS at this time, there has been an intense clinical interest in developing a treatment that is proven effective," said Dr. Scaglioni, who leads the Cancer Signaling Laboratory at the Simmons Cancer Center.
The team found that the enzymatic activity of ACSL3 (Acyl-CoA synthetase long-chain family member 3) is needed for the mutant KRAS gene to promote the formation of lung cancer, and further demonstrated that fatty acids, which are the substrates of ACSL3 enzyme, have a critical role in lung cancer.
"There is an urgent need for discovery of additional targets that inhibit lipid metabolism in cancer cells that could lead to targeted therapies: the discovery of the importance of ACSL3 in lung cancer meets this unmet need," said Dr. Mahesh S. Padanad, first author and part of the UT Southwestern team, which also includes postdoctoral fellow Dr. Smita Rindhe, and Dr. Margherita Melegari, research associate.
The study, published in Cell Reports, used several complementary approaches, including cell lines, mice, and human patient tumor samples to understand the biological significance of ACSL3 in lung cancer.
The work was supported by the American Cancer Society Research Scholar grant, the Cancer Prevention and Research Institute of Texas (CPRIT), UT Southwestern Friends of the Comprehensive Cancer Center, the Gibson Foundation, Texas 4000, the National Cancer Institute, a Welch Foundation Research Grant, the NCI Lung Cancer SPORE grant, and the University of Texas MD Anderson Institutional Tissue Bank. UT Southwestern's Specialized Program of Research Excellence (SPORE) grant from the National Cancer Institute, now in its 18th year, is the largest thoracic oncology effort in the U.S.
Researchers from MD Anderson Cancer Center, and the Department of Veterans Affairs Palo Alto Health Care System in California also contributed to the study. UT Southwestern researchers involved in this study include:
- Dr. Jerry W. Shay, Professor of Cell Biology, who holds The Southland Financial Corporation Distinguished Chair in Geriatrics;
- Dr. John D. Minna, Professor and Director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, and Director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics, who holds the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology, and the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research;
- Dr. Jeffrey G. McDonald, Associate Professor of Molecular Genetics and in the Center for Human Nutrition;
- Dr. Ralph J. DeBerardinis, Chief of the Division of Pediatric Metabolism and Genetics, and Associate Professor with Children's Medical Center Research Institute at UT Southwestern (CRI), who holds the Joel B. Steinberg, M.D. Chair in Pediatrics.
Additional UT Southwestern researchers involved in this study include: Niranjan Venkateswaran, research associate in Internal Medicine; Dr. Matthew Mitsche, postdoctoral research fellow in the Eugene McDermott Center for Human Growth and Development and Department of Molecular Genetics; Dr. Chendong Yang, research scientist at CRI; Dr. Kimberly Batten, computational biologist in Cell Biology; and Dr. Kenneth E. Huffman, research scientist in the Hamon Center for Therapeutic Oncology Research.
UT Southwestern's Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated comprehensive cancer center in North Texas and one of just 45 NCI-designated comprehensive cancer centers in the nation. Simmons Cancer Center includes 13 major cancer care programs and its education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the National Cancer Institute as a National Clinical Trials Network Lead Academic Participating Site.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.
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Lori Sundeen Soderbergh