Journal article
CDK4/6 inhibition triggers anti-tumour immunity
S Goel, MJ Decristo, AC Watt, H Brinjones, J Sceneay, BB Li, N Khan, JM Ubellacker, S Xie, O Metzger-Filho, J Hoog, MJ Ellis, CX Ma, S Ramm, IE Krop, EP Winer, TM Roberts, HJ Kim, SS McAllister, JJ Zhao
Nature | NATURE PUBLISHING GROUP | Published : 2017
DOI: 10.1038/nature23465
Abstract
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 biopsi..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by a Career Development Award from the DF/HCC SPORE in Breast Cancer (National Institutes of Health (NIH) 2015 P50 CA, to S.G.), a Landry Cancer Biology Research Fellowship (to M.J.D.), a DOD Era of Hope award (W81XWH-14-1-0191 to S.S.M.), NIH (NCI) RO1 CA166284 (to S.S.M.), a Presidential Early Career Award for Scientists and Engineers (to S.S.M.), the Breast Cancer Research Foundation (to J.J.Z.), the DF/HCC SPORE in Breast Cancer (P50 CA168504, to I.E.K., E.P.W., T.M.R. and J.J.Z.), and NIH awards CA187918-02 (to T.M.R. and J.J.Z.), CA210057-01 (to J.J.Z.), and CA172461-04 (to J.J.Z.). We thank T. Laszewski, A. Molineaux, J. Almeida, the Nikon Imaging Center at Harvard Medical School, and Boston Children's Hospital Heme/Onc-HSCI Flow Cytometry facility for experimental assistance. We thank providers of reagents: pHAGE-deltaOVA-zsGreen plasmid (R. E. Tay, K. Wucherpfennig), LCMV-P14 transgenic mice (A. Cartwright, K. Wucherpfennig), CT-26 cell line (S. Elledge), and MMTV-PyMT-S2WTP3 cell line (A. Moller). We thank S. Stewart for advice.