Science - USA (2022-01-14)

inhibitors and PARP inhibitors in PDX-derived
cell lines ( 100 ). Such synergy was also reported
for ovarian cancer cells ( 101 ). Another study
found that inhibition of CDK4/6 resulted
in down-regulation of PARP levels ( 102 ).

Protection against
chemotherapy-induced toxicity

Administration of palbociclib to mice induced
reversible quiescence in hematopoietic stem/
progenitor cells (HSPCs). This effect protected
mice from myelosuppression after total-body
irradiation. Moreover, treatment of tumor-
bearing mice with CDK4/6 inhibitors together
with irradiation mitigated radiation-induced
toxicity without compromising the therapeu-
tic effect ( 103 ). Co-administration of a CDK4/6
inhibitor, trilaciclib, with cytotoxic chemo-
therapy (5-FU, etoposide) protected animals
from chemotherapy-induced exhaustion of
HSPCs, myelosuppression, and apoptosis of
bone marrow ( 60 , 104 ). These observations
led to phase 2 clinical trial, which evaluated
the effects of trilaciclib administered prior
to etoposide and carboplatin for treatment of
small-cell lung cancer. Trilaciclib improved
myelopreservation while having no adverse
effect on antitumor efficacy ( 105 ). A similar
phase 2 clinical trial investigating trilaciclib in
combination with gemcitabine and carboplatin
chemotherapy in patients with metastatic
triple-negative breast cancer (TNBC) did not
observe a significant difference in myelosup-
pression. However, this study demonstrated
an overall survival benefit of the combination
therapy ( 106 , 107 ).

Metabolic function of CDK4/6 in cancer cells

TheroleofCDK4/6intumormetabolismis
only starting to be appreciated (Fig. 2A). Treat-
ment of pancreatic cancer cells with CDK4/6
inhibitors was shown to induce tumor cell
metabolic reprogramming ( 108 ). CDK4/6 inhi-
bition increased the numbers of mitochondria
and lysosomes, activated mTOR, and increased
the rate of oxidative phosphorylation, likely
through an RB1-dependent mechanism ( 108 ).
Combined inhibition of CDK4/6 and mTOR
strongly suppressed tumor cell proliferation
( 108 ). Moreover, CDK4/6 can phosphorylate
and inactivate TFEB, the master regulator of
lysosomogenesis, and through this mecha-
nism reduce lysosomal numbers. Conversely,
CDK4/6 inhibition activated TFEB and in-
creased the number of lysosomes ( 109 ). Another
mechanism linking CDK4/6 and lysosomes
was provided by the observation that treat-
ment of TNBC cells with CDK4/6 inhibitors
decreased mTORC1 activity and impaired the
recruitment of mTORC1 to lysosomes ( 110 ).
Consistent with the idea that mTORC1 inhib-
its lysosomal biogenesis, CDK4/6 inhibition
increased the number of lysosomes in tumor
cells. Because an increased lysosomal biomass

Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 6 of 19

A

Effector T cell Treg

CDK4/6i

G 1

S

G 2

M

IL2

IL2

IFNγ

N FAT

N FAT

NFκB

PD-L1

DNMT

ERV

dsRNA

MHC

class I

IFN

Type III IFN

Type III

CycD3

SPOP

CDK6

CycD

CDK4/6

P

P

RB1

P

CDK4/6i

Oxidative phosphorylation Mitochondria

Lysosomes

N

O

N

O

ADP

H+

H+

H+

H+

H+H+

H+ H+

AT P

P

PFKP PKM2

PPP and serine

pathways

GSH

ROS

Apoptosis

NADPH

P

mTORC1 mTORC1

TFEB

B

X

X

X

X

X

X

X X

X X

X

X

X

X

Fig. 2. CDK4 and CDK6: More than cell cycle kinases.Although the role of CDK4 and CDK6 in cell cycle

progression has been well documented, both kinases regulate several other functions that are only now

starting to be unraveled. (A) Inhibition of CDK4/6 (CDK4/6i) affects lysosome and mitochondrial numbers as

well as oxidative phosphorylation. Cyclin D3ÐCDK6 phosphorylates glycolytic enzymes 6-phosphofructokinase

(PFKP) and pyruvate kinase M2 (PKM2), thereby controlling ROS levels via the pentose phosphate (PPP)

and serine synthesis pathways. (B) Inhibition of CDK4/6 affects antitumor immunity, acting both within

cancer cells and on the immune system of the host. In tumor cells, inhibition of CDK4/6 impedes expression

of an E2F target, DNA methyltransferase (DNMT). DNMT inhibition reduces methylation of endogenous

retroviral genes (ERV) and increases intracellular levels of double-stranded RNA (dsRNA) ( 114 ). In effector

T cells, inhibition of CDK4/6 stimulates NFAT transcriptional activity and enhances secretion of IFN-gand

interleukin 2 (IL-2) ( 115 ).

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