Lung cancer cells susceptible to inhibitor treatment via newly discovered pathway
Next-generation cyclin dependent kinase 2/9 (CDK2/9) inhibitors offer a novel way to treat lung cancer with minimal toxic side effects on normal cells, according to a laboratory study by researchers at The University of Texas MD Anderson Cancer Center. The examined inhibitors were effective in stopping growth of lung cancer cells through induced anaphase catastrophe, a cellular pathway discovered at MD Anderson.
One of these highly active anti-cancer agents was CCT68127, a pre-clinical stage CDK2/9 inhibitor that was developed by Cyclacel Pharmaceuticals, Inc. (Cyclacel). It offers an innovative approach to combat aneuploid cancer cells. These are cancer cells that contain abnormal numbers of chromosomes. Aneuploidy occurs in virtually every cancer, but is particularly found in lung cancer. Aneuploidy is a hallmark for cancer development. About 90 percent of cancer cells in solid tumors and blood cancer are aneuploid. Study findings were replicated using Cyclacel’s clinical stage next generation CDK2/9 inhibitor, CYC065.
Research findings on how these new CDK2/9 inhibitors cause anaphase catastrophe, were published in the Feb. 10 online issue of the Journal of the National Cancer Institute. Anaphase catastrophe occurs when cells with extra cellular components called centrosomes fail to cluster the excessive centrosomes during cell division, leading to cancer cell death.
“CCT68127 showed anti-neoplastic effects in lung cancer cells from mice and humans, including those that result from the KRAS mutation, which represent an unmet medical need,” said Masanori Kawakami, M.D., Ph.D., postdoctoral fellow in Thoracic/Head and Neck Medical Oncology, and the first author on the JNCI paper. “Anaphase catastrophe spares normal cells which are not aneuploid, and the study provided the promising prospect of minimal side effects in mice, a finding that can be exploited in the cancer clinic.”
The drug inhibited growth up to 88 percent and induced cell death up to 43 percent in lung cancer cells through anaphase catastrophe with minimal effects on control non-cancerous cells. The study also revealed the cancer-causing gene KRAS’s sensitivity to CCT68127.
Cyclacel’s CCT68127 and CYC065 are new members of a class of drugs called CDK inhibitors. They play a critical role in regulating the cell cycle and have been linked to tumor development. The development of small-molecule inhibitors of CDKs as a method for cancer chemotherapy resulted in the introduction of CYC202, Cyclacel’s first generation CDK inhibitor. CCT68127 and CYC065, currently in a Phase 1 study are the next generation drugs being developed in the line of CDK cancer therapy inhibitors.
“Lung cancer is the most common cause of cancer-related mortality,” said Ethan Dmitrovsky, M.D., executive vice president and provost, and senior author of the JNCI paper. “Despite current treatments, the five-year survival rate of late-stage lung cancer is less than 20 percent. This next generation CDK study holds promise for future clinical studies of this novel class of agents.”
MD Anderson study team participants included Lisa Maria Mustachio, Ph.D., John Heymach, M.D., Ph.D., Faye Johnson, M.D., Ph.D., Lin Zheng, Ph.D., Carmen Behrens, M.D., and Xi Liu, Ph.D., all of Thoracic/Head and Neck Medical Oncology; Jaime Rodriguez-Canales, M.D., Barbara Mino, Pamela Villalobos, M.D. and Ignacio Wistuba, M.D., Translational Molecular Pathology; Jason Roszik, Ph.D., Melanoma Medical Oncology, Pan Tong, Ph.D. and Jing Wang, Ph.D., Bioinformatics and Computational Biology; and Jack Lee, Ph.D., Biostatistics.
Other participating institutions included the University of Illinois College of Pharmacy, Chicago; and Geisel School of Medicine at Dartmouth, Hanover, N.H.
The study was funded by the National Institutes of Health (R01-CA087546 and RO1-CA190722); the Samuel Waxman Cancer Research Foundation, UT-STARS award, the American Cancer Society, and philanthropic contributions to MD Anderson’s Lung Cancer Moon Shot Program.