At a glance
Study suggests CDK2 inhibitors, currently being tested to slow cell growth in a few types of cancer, could be used to reduce resistance to immunotherapy across a wider range of cancers.
Work identifies a previously unrecognized role for the cell-division protein CDK2 in shaping a tumor’s interaction with the immune system.
Combining a CDK2 inhibitor with immunotherapy extended survival and eliminated tumors in some mouse models of breast and colorectal cancer, including tumors that were completely resistant to immunotherapy alone.
Drugs called CDK2 inhibitors, which are currently being tested as treatments to slow the growth of a narrow range of cancers, may have hidden potential to reduce resistance to immunotherapy across a wide range of cancers, according to a preclinical study led by Harvard Medical School researchers at Dana-Farber Cancer Institute.
The study, published Sept. 2 in Molecular Cell, identifies a previously unrecognized role for CDK2 in shaping a tumor’s interaction with the immune system. In mice, blocking CDK2 helped immunotherapy drugs known as immune checkpoint inhibitors eradicate colorectal and breast tumors, including a form of triple-negative breast cancer that did not respond to immunotherapy alone.
“CDK2 inhibitors are being tested in clinical trials now, primarily in forms of ovarian and breast cancer known to require CDK2 for cancer cell growth,” said co-senior author Peter Sicinski, HMS professor of genetics at Dana-Farber. “But we’ve found that CDK2 inhibitors can be used in a way we did not expect, to overcome resistance to immune checkpoint inhibitors.”
Based on the findings, the team plans to pursue a clinical trial to determine whether CDK2 inhibition can safely improve responses to immune checkpoint inhibitors in humans.
A hidden genetic switch
Immune checkpoint inhibitors help the immune system recognize and attack cancer cells by blocking signals that restrain T cells. Basic research from HMS scientists in the 1990s and early 2000s helped establish the scientific foundation for these immunotherapies. However, some tumors resist the therapies, limiting their effectiveness.
CDK2, short for cyclin-dependent kinase 2, is a protein involved in cell division. It is activated by another protein called cyclin E. In some ovarian and breast cancers, unusually high levels of cyclin E make tumors dependent on CDK2 activity for growth. Several CDK2 inhibitors being tested in clinical trials focus on treating those cancers.
First author Chen Chu, HMS instructor in medicine at Dana-Farber, wanted to learn more about the function of CDK2 beyond cell division. He eliminated CDK2 from cancer cells and observed changes in gene expression that activate immune signaling, including genes known to be involved in how tumors respond to immunotherapy.
“The transcriptional changes were striking — the strongest effects involved genes that regulate interactions between tumor cells and the immune system,” said Chu. “This led us to ask whether CDK2 activity might contribute to resistance to immune checkpoint blockade.”
With more research, the team found that excessive activity of the cyclin E-CDK2 complex changes the behavior of BRD4, a protein that helps regulate gene activity. As a result, cancer cells produce lower levels of immune-related genes, including genes involved in processing and presenting tumor antigens and responding to interferons (signals that help coordinate immune activity).
These changes may make tumors less vulnerable to immune attack and therefore able to resist immune checkpoint inhibitors. Indeed, in an analysis using the Cancer Immunology Data Engine, a database that links immunotherapy outcomes in clinical trials with tumor gene-expression profiles, the team found that higher activity of cyclin E and CDK2 was associated with poorer responses to immune checkpoint blockade.
In mouse models of colon cancer and breast cancer, genetically disabling CDK2 or treating the animals with the CDK2 inhibitor tegtociclib plus an immune checkpoint inhibitor dramatically extended survival compared to either therapy alone. In some animals that responded to the combination, tumors vanished. The combination also showed activity in a model of triple-negative breast cancer that was completely resistant to immune checkpoint blockade.
Enlisting immune cells
The researchers found that CDK2 inhibition affects both cancer cells and immune cells called dendritic cells. In addition to making tumor cells more responsive to immune checkpoint blockade, CDK2 inhibition increased the number of dendritic cells in tumors and improved their ability to pick up fragments of tumor cells, called antigens, and present them to T cells, which use them to find and kill other cancer cells.
“There are two independent mechanisms that the CDK2 inhibitor is influencing against cancer,” explained Kai Wucherpfennig, the HMS Nancy Lurie Marks Professor of Neurology in the Field of Medical Oncology at Dana-Farber and co-senior author of the paper. “One is on cancer cells themselves, making them more sensitive to immune checkpoint blockade, and the other is on dendritic cells, making them more active.”
Finally, the team analyzed data from the Cancer Genome Atlas, a publicly available dataset of tumor gene activity from patients. Across several cancer types — including bladder, ovarian, uterine, colorectal, liver, lung, skin, and prostate cancers, as well as lymphoma — higher cyclin E-CDK2 activity was associated with lower activity of immune-related genes.
The results suggest that the strategy of sensitizing cancer to immunotherapy with CDK2 inhibition could be widely applicable. Further research, including clinical studies, will be needed.
Adapted from a Dana-Farber news release.
Authorship, funding, disclosures
Additional authors of the paper include Shanshan Zheng, Ning Mitchell, Zheqi Li, Xixi Zhang, Xiaowei Wu, Tian Zhang, Fabin Dang, Wojciech Michowski, Aleksandra Kolodziejczyk, Miranda L. Xu, Krzysztof W. Kotowski, Zhe Yang, Diego Martinez-Alonso, Joao Paulo, Jindan Sheng, Jane A. Kirby, Finn Groezinger, Yubin Zhou, Miao He, Yoshinaga Ito, Anushree C. Gulvady, Michael I. Cole, Pierre Foidart, Jun Nishida, Xiaohan Ning, Samanta Sharma, Jan M. Suski, Anne Fassl, Yu Zhou, Yan Geng, Wenyi Wei, Steven P. Gygi, and Kornelia Polyak.
This work was supported by the National Institutes of Health (grants R35CA305086, P01CA250959, GM067945, R01CA238039, R01CA251599, P01CA163222, P01CA236749, R00CA271370, R00CA263194, R50CA243769), the CRI Irvington Postdoctoral Fellowship (CRI4489), the Claudia Adams Barr Program for Innovative Basic Cancer Research Award, the Sara Elizabeth O’Brien Trust Postdoctoral Research Fellowship award, National Cancer Center fellowship grants, and a grant from the Kosciuszko Foundation.
Sicinski has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, Cedilla Therapeutics, Syros Pharmaceuticals, Blueprint Medicines, Curie.Bio, Differentiated Therapeutics, Exscientia, Ligature Therapeutics, Merck, Redesign Science, Scorpion Therapeutics, Serinus Biosciences, Sibylla Biotech, and Exo Therapeutics and has received research funding from Novartis. Sharma and Suski are currently employees of AstraZeneca, and Michowski is an employee of Enveda Biosciences. Wucherpfennig serves on scientific advisory boards of TScan Therapeutics, DEM BioPharma, Solu Therapeutics, and Nextech Invest and has received research funding from Novartis. He is a co-founder, scientific advisory board (SAB) member, and stockholder of Immunities, a biotech company. Polyak serves on the scientific advisory board of IDEAYA Biosciences, is an advisor for Curie.Bio, holds equity in Antares Therapeutics and stock options in IDEAYA Biosciences, receives research funding from Novartis, and has received honoraria from AstraZeneca and payment due to the acquisition of the mutant PIK3CA-selective inhibitor program of Scorpion Therapeutics by Eli Lilly in the past 24 months.
