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 post-doctoral 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.
Article: Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis, Mahesh S. Padanad, Georgia Konstantinidou, Niranjan Venkateswaran, Margherita Melegari, Smita Rindhe, Matthew Mitsche, Chendong Yang, Kimberly Batten, Kenneth E. Huffman, Jingwen Liu, Ximing Tang, Jaime Rodriguez-Canales, Neda Kalhor, Jerry W. Shay, John D. Minna, Jeffrey McDonald, Ignacio I. Wistuba, Ralph J. DeBerardinis, Pier Paolo Scaglioni, Cell Reports, doi: 10.1016/j.celrep.2016.07.009, published 28 July 2016.