Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM.
Glioblastoma multiforme (GBM) is a fatal primary brain tumor harboring myriad genetic and epigenetic alterations. The recent multidimensional analysis of the GBM genome has provided a more complete view of the landscape of such alterations and their linked pathways. This effort has demonstrated that certain pathways are universally altered, but that the specific genetic events altered within each pathway can vary for each particular patient's tumor. With this atlas of genetic and epigenetic events, it now becomes feasible to assess how the patterns of mutations in a pathway influence response to drugs that are targeting such pathways. This issue is particularly important for GBM because, in contrast to other tumor types, molecularly targeted therapies have failed to alter overall survival substantially. Here, we combined functional genetic screens and comprehensive genomic analyses to identify CDK6 as a GBM oncogene that is required for proliferation and viability in a subset of GBM cell lines and tumors. Using an available small molecule targeting cyclin-dependent kinases (CDKs) 4 and 6, we sought to determine if the specific pattern of retinoblastoma pathway inactivation dictated the response to CDK4/6 inhibitor therapy. We showed that codeletion of CDKN2A and CDKN2C serves as a strong predictor of sensitivity to a selective inhibitor of CDK4/6. Thus, genome-informed drug sensitivity studies identify a subset of GBMs likely to respond to CDK4/6 inhibition. More generally, these observations demonstrate that the integration of genomic, functional and pharmacologic data can be exploited to inform the development of targeted therapy directed against specific cancer pathways.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
W Ruprecht
WR
Wiedemeyer
Ian F
IF
Dunn
Steven N
SN
Quayle
Jianhua
J
Zhang
Milan G
MG
Chheda
Gavin P
GP
Dunn
Li
L
Zhuang
Joseph
J
Rosenbluh
Shujuan
S
Chen
Yonghong
Y
Xiao
Geoffrey I
GI
Shapiro
William C
WC
Hahn
Lynda
L
Chin
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism*
C493971:CDKN2C protein, human; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D010879:Piperazines; D011725:Pyridines; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib