CDK4/6 inhibition triggers anti-tumour immunity
Open accessAbstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a mouse model of breast cancer, CDK4/6 inhibition-driven cellular senescence also triggered antitumour immunity, mediated by suppression of regulatory T cells and re-expression of endogenous retroviral elements, which elicited an interferon response.
“Moreover, in a mouse model of breast cancer, CDK4/6 inhibition- driven cellular senescence also triggered antitumour immunity, mediated by suppression of regulatory Tcells and re- expression of endogenous retroviral elements, which elicited an interferon response 106,153 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [153]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCDK4/6 inhibitor-induced senescent non-malignant and malignant cells largely lack pro-inflammatory SASP factors.
“CDK4/6 inhibitor- induced senescent non- malignant and malignant cells largely lack pro- inflammatory SASP factors 111,153 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [153]
The main text (indexed under Abstract; page unavailable) says abemaciclib induced senescence-like features in tumor cells without increasing key SASP factors, as detailed in Extended Data Figure 8. The paper does not establish the same finding for non-malignant cells, so that extension is unsupported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDespite the marked reduction in the inflammatory SASP response, CDK4/6 inhibition triggers antitumour immunity and favours senescent cell removal.
“Importantly, despite the marked reduction in the inflammatory SASP response, CDK4/6 inhibition triggers antitumour immunity and favours senescent cell removal 111,153 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [153]
The paper reports that CDK4/6 inhibition promotes antitumour immunity and cytotoxic T-cell-mediated clearance of tumour cells (Abstract; page unavailable). It describes a senescence-like phenotype without increased expression of key SASP factors (main text and Extended Data Figure 8; pages unavailable), but does not establish a marked reduction in SASP or specifically show removal of senescent cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTargeted therapies such as EGFR inhibitors and CDK4/6 inhibitors can induce a strong reactivation of repeated elements in cancer cells, which results in cell death.
“Interestingly, targeted therapies such as EGFR inhibitors and CDK4/6 inhibitors can induce a strong reactivation of repeated elements in cancer cells, which results in cell death [24,102].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [102]
CDK4/CDK6 inhibitors stimulate immunity by promoting secretion of pro-inflammatory cytokines such as type III interferon and CCL5.
“CDK4/CDK6 inhibitors mediate immunostimulatory effects by favoring the secretion of pro-inflammatory cytokines such as type III interferon (Goel et al., 2017) and CC-chemokine ligand 5 (CCL5) (Vilgelm et al., 2016).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
In several preclinical tumor models, abemaciclib-mediated CDK4/CDK6 inhibition stimulates immunity by increasing MHC class I exposure on cancer cells.
“In various preclinical tumor models, CDK4/CDK6 inhibition with abemaciclib mediates immunostimulatory effects by promoting the exposure of MHC class I molecules on the cancer cell surface (Goel et al., 2017; Schaer et al., 2018).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
This cytokine secretion occurs either after endogenous retrovirus derepression and nucleic acid sensing or after permanent cell cycle blockage with a senescence-associated secretory phenotype.
“This occurs either upon the derepression of endogenous retroviruses and consequent nucleic acid sensing (Goel et al., 2017; Vanpouille-Box et al., 2019) or following the establishment of a permanent cell cycle blockage (i.e., cellular senescence) characterized by an abundant secretory component, the so-called senescence-associated secretory phenotype (SASP) (Jerby-Arnon et al., 2018).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
TREG cells express CDK4/CDK6 and VEGF receptors, making them especially sensitive to CDK4/CDK6 inhibitors and bevacizumab.
“TREG cells express CDK4/CDK6 as well as VEGF receptors (Goel et al., 2017; Terme et al., 2013) and hence are particularly sensitive to CDK4/CDK6 inhibitors and bevacizumab”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
The CDK4/CDK6-DNMT1-endogenous retroviral element-type III interferon pathway can be targeted with clinically used CDK4/CDK6 inhibitors.
“a pathway that can be actioned with clinically employed CDK4/ CDK6 inhibitors”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
Active CDK4/CDK6 signaling restricts DNMT1-driven expression of endogenous retroviral elements that would otherwise promote type III interferon secretion.
“active CDK4/CDK6 signaling limits the ability of DNMT1 to drive the expression of endogenous retroviral elements that would otherwise promote type III IFN secretion”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Goel et al., 2017
Treatment raises the count of CD3+ cells that enter the tumor mass, enabling cytotoxic T-cell stimulation.
“Consistent with this, the number of CD3+ cells recruited into the tumor mass increases after treatment, allowing for the stimulation of cytotoxic T-cells (CTLs).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Goel et al., 2017
CDK4 activity is needed for generating CD4+FOXP3+ regulatory T cells capable of inhibiting cytotoxic T-lymphocyte responses.
“Additionally, CDK4 is necessary for the development of CD4+FOXP3+ Treg cells that can suppress CTL responses.”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Goel et al., 2017
In several breast cancer models, including patient-derived xenografts and an MMTV-HER2 mouse, abemaciclib or palbociclib causes growth arrest and increased antigen processing and presentation in tumor cells.
“Recently, in a variety of breast cancer models, including patient-derived xenografts and an MMTV-HER2 mouse, it was demonstrated that abemaciclib or palbociclib induces growth arrest and up-regulation of antigen processing and presentation in the tumor cells (Goel et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Goel et al., 2017
Animals with CDK4 deficiency, with or without tumors, have lower numbers of infiltrating and circulating CD4+FOXP3+ regulatory T cells, while other T-cell subsets are largely unaffected.
“In both tumor bearing and non-tumor bearing animals, CDK4 deficiency is associated with a reduced number of infiltrating and circulating CD4+FOXP3+ Treg cells with minimal impact on other T-cell subsets (Chow et al., 2010; Goel et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Goel et al., 2017
PI3K inhibitors and CDK4/6 inhibitors have been tested in preclinical models to reverse signaling defects and metabolic stress to enhance immune checkpoint blockade response.
“Several other strategies have been tested in preclinical models to reverse signaling defects and metabolic stress in order to enhance response to ICB including PI3K inhibitors (Marijt et al., 2019), and cyclin-dependent kinase 4 and 6 (CDK4/6) (Goel et al., 2017)”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Goel et al., 2017
Novel approved drugs, including PARP inhibitors and CDK4/6 inhibitors, might potentiate the effectiveness of immunotherapies, in part, by vascular normalization.
“novel approved drugs, including poly [ADP-ribose] polymerase inhibitors and cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors, might potentiate the effectiveness of immunotherapies, in part, by vascular normalization119.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [119]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455 · see citing works
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160 · see citing works
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
CDK inhibitors: positive and negative regulators of G1-phase progression
Sherr, C. J., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.12.1501 · Cited by 6,115 · see citing works
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
Palbociclib and letrozole in advanced breast cancer
Finn, R. S., Martin, M., Rugo, H. S., Jones, S., Im, S.-A., Gelmon, K., Harbeck, N., Lipatov, O. N., Walshe, J. M., Moulder, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1607303 · Cited by 3,007 · see citing works
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072 · see citing works
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.011 · Cited by 2,022 · see citing works
Roulois, D., Loo Yau, H., Singhania, R., Wang, Y., Danesh, A., Shen, S. Y., Han, H., Liang, G., Jones, P. A., Pugh, T. J., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.056 · Cited by 1,527 · see citing works
Finn, R. S., Dering, J., Conklin, D., Kalous, O., Cohen, D. J., Desai, A. J., Ginther, C., Atefi, M., Chen, I., Fowst, C., et al. (2009) · Breast Cancer Research · doi:10.1186/bcr2419 · Cited by 1,398 · see citing works
Bates, G. J., Fox, S., Han, C., Leek, R., García, J. F., Harris, A., & Banham, A. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.05.9584 · Cited by 1,209 · see citing works
Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6
Malumbres, M., Sotillo, R., Santamarı́a, D., Galán, J., Cerezo, A., Ortega, S., Dubus, P., & Barbacid, M. (2004) · Cell · doi:10.1016/j.cell.2004.08.002 · Cited by 793 · see citing works
Patnaik, A., Rosen, L. S., Tolaney, S. M., Tolcher, A. W., Goldman, J. W., Gandhi, L., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Hilton, J. F., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0095 · Cited by 743 · see citing works
CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer
Wang, Y., Zhang, T., Kwiatkowski, N. P., Abraham, B. J., Lee, T. I., Xie, S., Yuzugullu, H., Von, T., Li, H., Lin, Z., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.063 · Cited by 471 · see citing works
Self-citationOvercoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Goel, S., Wang, Q., Watt, A. C., Tolaney, S. M., Dillon, D. A., Li, W., Ramm, S., Palmer, A. C., Yuzugullu, H., Varadan, V., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.006 · Cited by 470 · see citing works
Self-citationSystemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin
McAllister, S. S., Gifford, A. M., Greiner, A. L., Kelleher, S. P., Saelzler, M. P., Ince, T. A., Reinhardt, F., Harris, L. N., Hylander, B. L., Repasky, E. A., et al. (2008) · Cell · doi:10.1016/j.cell.2008.04.045 · Cited by 431 · see citing works
Self-citationRequirement for CDK4 kinase function in breast cancer
Yu, Q., Sicinska, E., Geng, Y., Ahnström, M., Zagozdzon, A., Kong, Y., Gardner, H., Kiyokawa, H., Harris, L. N., Stål, O., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2005.12.012 · Cited by 429 · see citing works
Ma, C. X., Gao, F., Luo, J. R., Northfelt, D., Goetz, M. P., Forero, A., Hoog, J., Naughton, M., Ademuyiwa, F. O., Suresh, R., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3206 · Cited by 367 · see citing works
Self-citationThe Requirement for Cyclin D Function in Tumor Maintenance
Choi, Y. J., Li, X., Hydbring, P., Sanda, T., Stefano, J., Christie, A. L., Signoretti, S., Look, A. T., Kung, A. L., von Boehmer, H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.09.015 · Cited by 342 · see citing works
Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction
Bauer, C. A., Kim, E. Y., Marangoni, F., Carrizosa, E., Claudio, N., & Mempel, T. R. (2014) · Journal of Clinical Investigation · doi:10.1172/jci66375 · Cited by 238 · see citing works
Obata, Y., Furusawa, Y., Endo, T. A., Sharif, J., Takahashi, D., Atarashi, K., Nakayama, M., Onawa, S., Fujimura, Y., Takahashi, M., et al. (2014) · Nature Immunology · doi:10.1038/ni.2886 · Cited by 175 · see citing works
Relevance of the Tumor Antigen in the Validation of Three Vaccination Strategies for Melanoma
Bellone, M., Cantarella, D., Castiglioni, P., Crosti, M., Ronchetti, A. B., Moro, M., Garancini, M. P., Casorati, G., & Dellabona, P. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.5.2651 · Cited by 137 · see citing works
Ni, J., Ramkissoon, S. H., Xie, S., Goel, S., Stover, D. G., Guo, H., Luu, V., Marco, E., Ramkissoon, L. A., Kang, Y. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4120 · Cited by 122 · see citing works
Self-citationKimura, H. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg406 · Cited by 93 · see citing works
Gimenez, J., Montgiraud, C., Oriol, G., Pichon, J.-P., Ruel, K., Tsatsaris, V., Gerbaud, P., Frendo, J., Evain‐Brion, D., & Mallet, F. (2009) · DNA Research · doi:10.1093/dnares/dsp011 · Cited by 73 · see citing works
Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy
Wong, C. S. F., Sceneay, J., House, C. M., Halse, H. M., Liu, M. C. P., George, J., Hunnam, T. C. U. P., Parker, B. S., Haviv, I., Ronai, Z. A., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3310 · Cited by 54 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [19]Heng TS Painter MW Immunological Genome Project, C. The Immunological Genome Project: networks of gene expression in immune cells Nat Immunol 9 1091 1094 10.1038/ni1008-1091 2008 18800157 · DOI · Paper page
Cited by
Sorted by citations
Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., & Jain, R. K. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.29 · Cited by 2,027 · see citing works
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · see citing works
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade
Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., Leeson, R., Kanodia, A., Mei, S., Lin, J.-R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.006 · Cited by 1,429 · see citing works
Mechanisms of resistance to immune checkpoint inhibitors
Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.434 · Cited by 1,383 · see citing works
Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., et al. (2018) · Nature · doi:10.1038/nature25015 · Cited by 1,013 · see citing works
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
Ishizuka, J. J., Manguso, R. T., Cheruiyot, C. K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B. C., Du, P. P., Yates, K. B., Dubrot, J., et al. (2019) · Nature · doi:10.1038/s41586-018-0768-9 · Cited by 697 · see citing works
MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer
Johnston, S., Martin, M., Di Leo, A., Im, S.-A., Awada, A., Forrester, T., Frenzel, M., Hardebeck, M. C., Cox, J., Barriga, S., et al. (2019) · npj Breast Cancer · doi:10.1038/s41523-018-0097-z · Cited by 685 · see citing works
Combination strategies to maximize the benefits of cancer immunotherapy
Zhu, S., Zhang, T., Zheng, L., Liu, H., Song, W., Liu, D., Li, Z., & Pan, C.-X. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01164-5 · Cited by 654 · see citing works
Schaer, D. A., Beckmann, R. P., Dempsey, J. A., Huber, L., Forest, A., Amaladas, N., Li, Y., Wang, Y. C., Rasmussen, E. R., Chin, D., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.053 · Cited by 469 · see citing works
Genomic correlates of response to immune checkpoint blockade
Keenan, T. E., Burke, K. P., & Van Allen, E. M. (2019) · Nature Medicine · doi:10.1038/s41591-019-0382-x · Cited by 448 · see citing works
NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination
Ruscetti, M., Leibold, J., Bott, M. J., Fennell, M., Kulick, A., Salgado, N. R., Chen, C.-C., Ho, Y.-J., Sanchez-Rivera, F. J., Feucht, J., et al. (2018) · Science · doi:10.1126/science.aas9090 · Cited by 415 · see citing works
Wanderley, C. W., Colón, D. F., Luiz, J. P. M., Oliveira, F. F., Viacava, P. R., Leite, C. A., Pereira, J. A., Silva, C. M., Silva, C. R., Silva, R. L., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3480 · Cited by 420 · see citing works
Current Landscape of Immunotherapy in Breast Cancer: A Review
Adams, S., Gatti-Mays, M. E., Kalinsky, K., Korde, L. A., Sharon, E., Amiri-Kordestani, L., Bear, H., McArthur, H. L., Frank, E., Perlmutter, J., et al. (2019) · JAMA Oncology · doi:10.1001/jamaoncol.2018.7147 · Cited by 384 · see citing works
Self-citationCDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought
Klein, M. E., Kovatcheva, M., Davis, L. E., Tap, W. D., & Koff, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.023 · Cited by 378 · see citing works
CDK4/6 inhibition in breast cancer: current practice and future directions
Pernas, S., Tolaney, S. M., Winer, E. P., & Goel, S. (2018) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835918786451 · Cited by 316 · see citing works
Self-citationEndogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma
Smith, C. C., Beckermann, K. E., Bortone, D. S., De Cubas, A. A., Bixby, L. M., Lee, S. J., Panda, A., Ganesan, S., Bhanot, G., Wallen, E. M., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci121476 · Cited by 303 · see citing works
The double dealing of cyclin D1
Tchakarska, G., & Sola, B. (2020) · Cell Cycle · doi:10.1080/15384101.2019.1706903 · Cited by 278 · see citing works
Frangieh, C. J., Melms, J. C., Thakore, P. I., Geiger-Schuller, K. R., Ho, P., Luoma, A. M., Cleary, B., Jerby-Arnon, L., Malu, S., Cuoco, M. S., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00779-1 · Cited by 276 · see citing works
Cellular senescence: Immunosurveillance and future immunotherapy
Burton, D. G. A., & Stolzing, A. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.02.001 · Cited by 221 · see citing works
Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression
Hossain, D. M. S., Javaid, S., Cai, M., Zhang, C., Sawant, A., Hinton, M., Sathe, M., Grein, J., Blumenschein, W., Pinheiro, E. M., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94586 · Cited by 216 · see citing works
Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
Zhou, X., Singh, M., Sanz Santos, G., Guerlavais, V., Carvajal, L. A., Aivado, M., Zhan, Y., Oliveira, M. M. S., Westerberg, L. S., Annis, D. A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1741 · Cited by 169 · see citing works
Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce
Li, Q., Hagberg, C. E., Silva Cascales, H., Lang, S., Hyvönen, M. T., Salehzadeh, F., Chen, P., Alexandersson, I., Terezaki, E., Harms, M. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01501-8 · Cited by 178 · see citing works
Zhang, Q.-F., Li, J., Jiang, K., Wang, R., Ge, J.-L., Yang, H., Liu, S.-J., Jia, L.-T., Wang, L., & Chen, B.-L. (2020) · Theranostics · doi:10.7150/thno.44871 · Cited by 177 · see citing works
Immunomodulation by anticancer cell cycle inhibitors
Petroni, G., Formenti, S. C., Chen-Kiang, S., & Galluzzi, L. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0300-y · Cited by 163 · see citing works
Diekman, B. O., Sessions, G. A., Collins, J. A., Knecht, A. K., Strum, S. L., Mitin, N. K., Carlson, C. S., Loeser, R. F., & Sharpless, N. E. (2018) · Aging Cell · doi:10.1111/acel.12771 · Cited by 158 · see citing works
Senescence as a therapeutically relevant response to CDK4/6 inhibitors
Wagner, V., & Gil, J. (2020) · Oncogene · doi:10.1038/s41388-020-1354-9 · Cited by 148 · see citing works
Zhai, J., Gu, X., Liu, Y., Hu, Y., Jiang, Y., & Zhang, Z. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1152934 · Cited by 131 · see citing works
Pharmacological CDK4/6 inhibition reveals a p53‐dependent senescent state with restricted toxicity
Wang, B., Varela‐Eirin, M., Brandenburg, S. M., Hernandez‐Segura, A., van Vliet, T., Jongbloed, E. M., Wilting, S. M., Ohtani, N., Jager, A., & Demaria, M. (2022) · The EMBO Journal · doi:10.15252/embj.2021108946 · Cited by 113 · see citing works
Stopfer, L. E., Mesfin, J. M., Joughin, B. A., Lauffenburger, D. A., & White, F. M. (2020) · Nature Communications · doi:10.1038/s41467-020-16588-9 · Cited by 109 · see citing works
Whittle, J. R., Vaillant, F., Surgenor, E., Policheni, A. N., Giner, G., Capaldo, B. D., Chen, H.-R., Liu, H. K., Dekkers, J. F., Sachs, N., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1872 · Cited by 102 · see citing works
Yu, J., Yan, J., Guo, Q., Chi, Z., Tang, B., Zheng, B., Yu, J., Yin, T., Cheng, Z., Wu, X., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0475 · Cited by 100 · see citing works
Lysosomal trapping of palbociclib and its functional implications
Llanos, S., Megias, D., Blanco-Aparicio, C., Hernández-Encinas, E., Rovira, M., Pietrocola, F., & Serrano, M. (2019) · Oncogene · doi:10.1038/s41388-019-0695-8 · Cited by 96 · see citing works
Yin, T., Zhao, Z.-B., Guo, J., Wang, T., Yang, J.-B., Wang, C., Long, J., Ma, S., Huang, Q., Zhang, K., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3397 · Cited by 92 · see citing works
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
Laderian, B., & Fojo, T. (2017) · Seminars in Oncology · doi:10.1053/j.seminoncol.2018.03.006 · Cited by 77 · see citing works
SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
Wang, Y., Mohseni, M., Grauel, A., Diez, J. E., Guan, W., Liang, S., Choi, J. E., Pu, M., Chen, D., Laszewski, T., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-80999-x · Cited by 73 · see citing works
Lelliott, E. J., McArthur, G. A., Oliaro, J., & Sheppard, K. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661737 · Cited by 65 · see citing works
Cell Fate Reprogramming in the Era of Cancer Immunotherapy
Zimmermannova, O., Caiado, I., Ferreira, A. G., & Pereira, C.-F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.714822 · Cited by 56 · see citing works
Biomarkers for Response to Immune Checkpoint Blockade
Ganesan, S., & Mehnert, J. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033604 · Cited by 51 · see citing works
Teh, J. L. F., Erkes, D. A., Cheng, P. F., Tiago, M., Wilski, N. A., Field, C. O., Chervoneva, I., Levesque, M. P., Xu, X., Dummer, R., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0743 · Cited by 22 · see citing works
- Authors
- Goel, S., DeCristo, M. J., Watt, A. C., BrinJones, H., Sceneay, J., Li, B. B., Khan, N., Ubellacker, J. M., Xie, S., Metzger-Filho, O., Hoog, J., Ellis, M. J., Ma, C. X., Ramm, S., Krop, I. E., Winer, E. P., Roberts, T. M., Kim, H.-J., McAllister, S. S., & Zhao, J. J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Washington University in St. Louis (US)
- Baylor College of Medicine (US)
- Harvard University (US)
- Broad Institute (US)
- Corresponding author
- Goel, Shom
- McAllister, Sandra S.
- Zhao, Jean J.
- ORCID
- Venue
- Nature
- Published
- 2017-08
- Volume
- 548
- Issue
- 7668
- Pages
- 471-475
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5570667
- OpenAlex
- W2750328162
- Cited by
- 1,513
- References
- 29
- Citations by year
- 2026: 132 · 2025: 165 · 2024: 187 · 2023: 190 · 2022: 219 · 2021: 203 · 2020: 171 · 2019: 129 · 2018: 100 · 2017: 16
- FWCI
- 50.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA166284, R01CA172461, R01CA187918, P50CA168504, R35CA210057)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CDK4/6 inhibitors, antitumor immunity, breast cancer, tumor immunogenicity, tumor antigen presentation, regulatory T cells, DNMT1, DNA methylation, endogenous retroviruses, interferon lambda, double-stranded RNA, immune checkpoint blockade, cytotoxic T lymphocytes, E2F transcription factors, combination immunotherapy
- MeSH terms
- Biological Mimicry, Animals, Breast Neoplasms, Disease Models, Animal, Female, Humans, Interferons, Phosphorylation, Repressor Proteins, RNA, Double-Stranded, Viruses, Signal Transduction, Antigen Presentation, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, T-Lymphocytes, Regulatory, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Cell Cycle Checkpoints, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
