revealed that lysosomotropic agents that re-
verse the lysosomal sequestration (such as
chloroquine, azithromycin, or siramesine)
render TNBC cells fully sensitive to CDK4/6
inhibition ( 71 , 111 ). These observations now
need to be tested in clinical trials for TNBC
patients.
Outlook
Although D-cyclins and CDK4/6 were dis-
covered 30 years ago, several aspects of cyclin
D–CDK4/6 biology, such as their role in
antitumor immunity, are only now starting
to be appreciated. The full range of cyclin
D–CDK4/6 functions in tumor cells remains
unknown. It is likely that these kinases play
a much broader role in cancer cells than is
currently appreciated. Hence, the impact
of CDK4/6 inhibition on various aspects of
tumorigenesis requires further study. Also,
treatment of patients with CDK4/6 inhib-
itors likely affects several aspects of host
physiology, which may be relevant to cancer
progression.
In the next years, we will undoubtedly wit-
ness the development and testing of new
CDK4/6 inhibitors. Because activation of CDK2
represents a frequent CDK4/6 inhibitor resist-
ance mechanism, compounds that inhibit
CDK4/6 and CDK2 may prevent or delay the
development of resistance. Conversely, selec-
tive compounds that inhibit CDK4 but not
CDK6 may allow more aggressive dosing, as
they are expected not to result in bone marrow
toxicity caused by CDK6 inhibition. New, less
basic CDK4/6 inhibitor compounds ( 111 ) may
Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 16 of 19
CDK4/6 inhibitor
resistance
Lysosomal sequestration
OOONN
OOONNN OOONN
OON
OOONN
OONN
CycD
CDK4/6
E2F
RB1
P
E2F
RB1
CycDON
CDK4/6
CycDON
CDK4/6
CycD
CDK4/6
Activation of pathways impinging
on CycD-CDK4/6
CDK6 CycD1
FGFR
PI3K
AKT
mTOR
EGFR
EGF
FGF
Ras
RAF
MEK
ERK
CycD
CDK2
CycD
CDK4/6
E2F
RB1
P
E2F
RB1 CycD
CDK4/6
CDK4/6 up-regulation/amplification
CycD
CDK4/6
CycD
CDK4/6
CycD
CDK4/6
E2F
RB1
RB1E2F P
FAT^1
MST1/2
L ATS1/2
YAP/ TATEADZ CDK6
YAP/ TAZ
miR
432-5p
miR 432-5p
SMAD4
miR
432-5p
CDK6
CDK6
CDK4
RB1
E2F
RB1 loss
CycE-CDK2 activation
CycE
CDK2
CycE CycE
CDK2
E2F
RB1
E2F P
RB1
p27
p21
CycE
CDK2
PI3K
PDK1
mTOR
AKT
CycE
PTEN
CDK2
X
X X
X X
X
X
X
X
X
Fig. 3. Mechanisms of cancer cell resistance to CDK4/6 inhibition.Known mechanisms include loss of RB1, activation of pathways impinging on CycD-CDK4/6,
amplification of theCDK4/6genes and overexpression of CDK6 protein, activation of CycE-CDK2, and lysosomal sequestration of CDK4/6 inhibitors. Blank pieces
of the puzzle denote additional mechanisms that remain to be discovered.
RESEARCH | REVIEW