REVIEW SUMMARY
◥CANCER
CDK4 and CDK6 kinases: From basic
science to cancer therapy
Anne Fassl, Yan Geng, Piotr Sicinski*
BACKGROUND:Cyclins and cyclin-dependent
kinases (CDKs) drive cell division. Of par-
ticular importance to the cancer field are
D-cyclins, which activate CDK4 and CDK6. In
normal cells, the activity of cyclin D–CDK4/6 is
controlled by the extracellular pro-proliferative
or inhibitory signals. By contrast, in many can-
cers, cyclin D–CDK4/6 kinases are hyperacti-
vated and become independent of mitogenic
stimulation, thereby driving uncontrolled tumor
cell proliferation. Mouse genetic experiments
established that cyclin D–CDK4/6 kinases are
essential for growth of many tumor types, and
they represent potential therapeutic targets.
Genetic and cell culture studies documented
thedependenceofbreastcancercellsonCDK4/6.
Chemical CDK4/6 inhibitors were synthesized
and tested in preclinical studies. Introduction
of these compounds to the clinic represented a
breakthrough in breast cancer treatment and
will likely have a major impact on the treat-
ment of many other tumor types.ADVANCES:Small-molecule CDK4/6 inhibitors
(palbociclib, ribociclib, abemaciclib) showed
impressive results in clinical trials for patientswith hormone receptor–positive breast cancers.
Addition of CDK4/6 inhibitors to standard
endocrine therapy substantially extended me-
dian progression-free survival and prolonged
median overall survival. Consequently, all three
CDK4/6 inhibitors have been approved for
treatment of women with advanced or meta-
static hormone receptor–positive breast cancers.
In the past few years, the renewed interest in
CDK4/6 biology has yielded several surpris-
ing discoveries. The emerging concept is that
CDK4/6 kinases regulate a much wider set
of cellular functions than anticipated. Conse-
quently, CDK4/6 inhibitors, beyond inhibiting
tumor cell proliferation, affect tumor cells and
the tumor environment through mechanisms
that are only beginning to be elucidated. For
example, inhibition of CDK4/6 affects anti-
tumor immunity acting both on tumor cells
and on the host immune system. CDK4/6 in-
hibitors were shown to enhance the efficacy of
immune checkpoint blockade in preclinical
mouse cancer models. These new concepts are
now being tested in clinical trials.OUTLOOK:Palbociclib, ribociclib, and abemaciclib
are being tested in more than 300 clinical trials
for more than 50 tumor types. These trials
evaluate CDK4/6 inhibitors in combination
with a wide range of therapeutic compounds
that target other cancer-relevant pathways.
Several other combination treatments were
shown to be efficacious in preclinical studies and
will enter clinical trials soon. Another CDK4/6
inhibitor, trilaciclib, is being tested for its
ability to shield normal cells of the host from
cytotoxic effects of chemotherapy. New CDK4/6
inhibitors have been developed and are being
assessed in preclinical and clinical trials. The
major impediment in the therapeutic use of
CDK4/6 inhibitors is that patients who ini-
tially respond to treatment often develop
resistance and eventually succumb to the
disease. Moreover, a substantial fraction of
tumors show preexisting, intrinsic resistance
to CDK4/6 inhibitors. One of the main chal-
lenges will be to elucidate the full range of
resistance mechanisms. Even with the current,
limited knowledge, one can envisage the prin-
ciples of new, improved approaches to over-
come known resistance mechanisms. Another
largely unexplored area for future study is the
possible involvement of CDK4/6 in other path-
ologic states beyond cancer. This will be the
subject of intense studies, and it may extend
the utility of CDK4/6 inhibitors to the treat-
ment of other diseases.
▪RESEARCH
158 14 JANUARY 2022•VOL 375 ISSUE 6577 science.orgSCIENCE
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
Cite this article as A. Fasslet al.,Science 375 , eabc1495
(2022). DOI: 10.1126/science.abc1495READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.abc1495Cancer TreatmentCombination treatment ResistanceIGFREGFR
FGFRHER2
PI3KmTORRB1P
E2FCycD
CDK4/6CycD
CDK4/6CycD
CDK4/6E2FRB1CDK4/6
inhibitor
O N
O NO N
O NRB1PE2FCycDO
CDK4/6CycDOO
CycDOO CDK4/6
CDK4/6E2FRB1RB1P
E2FE2FRB1CDK4/6
inhibitor
O N
O NO N
O NRB1P
E2FCycD
CDK4/6OO
CycD
CycDOO CDK4/6
CDK4/6O NO N
CycD
CDK4/6CycDOO
CDK4/6E2FRB1RB1
E2FCycD
CDK4/6G 1G 2 SMXXX
XXXXTargeting cyclin DÐCDK4/6 for cancer treatment.D-cyclins (CycD) activate CDK4 and CDK6 in G 1 phase
of the cell cycle and promote cell cycle progression by phosphorylating the retinoblastoma protein RB1.
RB1 inhibits E2F transcription factors; phosphorylation of RB1 activates E2F-driven transcription. In many
cancers, CycD-CDK4/6 is constitutively activated and drives uncontrolled cell proliferation. The development
of small-molecule CDK4/6 inhibitors provided a therapeutic tool to repress constitutive CycD-CDK4/6
activity and to inhibit cancer cell proliferation. As with several targeted therapies, tumors eventually develop
resistance and resume cell proliferation despite CDK4/6 inhibition. New combination treatments,
involving CDK4/6 inhibitors plus inhibition of other pathways, are being tested in the clinic to delay or
overcome the resistance.