Mutations of the KRAS gene are commonly known to lead to cancer. However, deeper understanding of exactly how they do this continues to be explored by cancer researchers.
Scientists at The University of Texas MD Anderson Cancer Center have gained further insight about the processes behind KRAS mutations through a study that identified three subsets of lung cancer with mutations in this gene. This line of research has the potential to open up new approaches for treatment of lung adenocarcinoma (LUAC), the most common form of lung cancer.
The data was presented on April 19 at the 2015 American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.
"The development of more effective treatments for LUAC-bearing activating mutations in KRAS has been hampered by the biological heterogeneity of KRAS-mutant tumors," said John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology. "The molecular underpinnings that drive this process are poorly characterized."
Heymach and his study team adopted an integrated approach to the discovery of biologically distinct subsets of KRAS-mutant LUAC and explored their molecular vulnerabilities.
"Our work revealed three major subsets of KRAS-mutant LUAC, which were dominated by co-occurring genetic events, each biologically distinct and susceptible to different therapeutic strategies," said Ferdinandos Skoulidis, M.D., Ph.D., instructor of Thoracic/Head & Neck Medical Oncology.
The study used data from The Cancer Genome Atlas and other sources including the MD Anderson-led trial, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) to identify three robust subsets of KRAS-mutant LUAC. Each of the subsets, KL, KP and KC, demonstrated unique intracellular signaling patterns. KL in particular showed enhanced sensitivity to several Hsp90 inhibitors, drugs that have shown therapeutic promise. In this case, an Hsp90 inhibitor called ganetespib appeared particularly effective.
MD Anderson study team members included Lauren Byers, M.D., Vassiliki Papadimitrakopoulou, M.D., Carmen Behrens, M.D., Uma Giri, Ph.D., Jayanthi Gudikote, Ph.D., You Hong Fan, and Waun Ki Hong, M.D., all of Thoracic/Head & Neck Medical Oncology; Lixia Diao, Ph.D., Pan Tong, Ph.D., John Weinstein, M.D., Ph.D., and Jing Wang, Ph.D., all of Bioinformatics & Computational Biology; Jianjun Zhang, Ph.D., and Andrew Futreal, Ph.D., Genomic Medicine; Humam Kadara, Ph.D., Edwin Parra, Ph.D., Jaime Rodriguez-Canales, M.D., Julie Izzo, M.D. and Ignacio Wistuba, M.D., all of Translational Molecular Pathology; Maria Angelica Cortez, Ph.D., Experimental Radiation Oncology; Jianhua Zhang, Ph.D., Timothy Hefferan, Ph.D., and Carlo Toniatti, M.D., Ph.D., Institute for Applied Cancer Science; Padmanee Sharma, M.D., Ph.D., Genitourinary Medical Oncology; Gordon Mills, M.D., Ph.D., Systems Biology; and James Allison, Ph.D., Immunology.
Other participating institutions included The University of Texas Southwestern Medical Center, Dallas; Wexner Medical Center, Ohio State University, Columbus, Ohio; Seoul National University, Republic of Korea; Foundation Medicine, Cambridge, Mass.; Yale Cancer Center, New Haven, Conn.; and Dana Farber Cancer Institute, Boston.
The study was funded by the National Institutes of Health (P50 CA070907, R01 CA 155196-01A1, CA016672, and 1R01 CAQ168484-01), The V Foundation For Cancer Research, Ms. Jane A. Ford, the Jeannine T. Rainbolt Advanced Scholars Endowment, the Eric and Pat Bodin Cancer Research Fellowship, and the Uniting Against Lung Cancer Legacy Program for Advances in Lung Cancer Research Program.