Science - USA (2022-01-14)

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