escape lysosomal sequestration and may be ef-
ficacious against resistant cancer types such as
TNBC. Degrader compounds, which induce pro-
teolysis of cyclin D rather than inhibit cyclin
D–CDK4/6 kinase, may have superior proper-
ties, as they would extinguish both CDK4/6-
dependent and -independent functions of
D-cyclins in tumorigenesis. Moreover, dissolu-
tion of cyclin D–CDK4/6 complexes is expected
to liberate KIP/CIP inhibitors, which would
then inhibit CDK2. D-cyclins likely play CDK-
independent functions in tumorigenesis—for
example, by regulating gene expression ( 166 ).
However, their role in tumor biology and the
utility of targeting these functions for cancer
treatment remain largely unexplored.
An important challenge will be to test and
identify combinatorial treatments involving
CDK4/6 inhibitors for the treatment of differ-
ent tumor types. CDK4/6 inhibitors trigger cell
cycle arrest of tumor cells and, in some cases,
senescence. It will be essential to identify com-
bination treatments that convert CDK4/6 in-
hibitors from cytostatic compounds to cytotoxic
ones, which would unleash the killing of tumor
cells. Genome-wide high-throughput screens
along with analyses of mouse cancer models
andPDXswillhelptoaddressthispoint.
Another largely unexplored area of cyclin D–
CDK4/6 biology is the possible involvement
of these proteins in other pathologies, such
as metabolic disorders. Research in this area
may extend the use of CDK4/6 inhibitors to
treatment of other diseases. All these un-
resolved questions ensure that CDK4/6 biology
will remain an active area of basic, translational,
and clinical research for several years to come.
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