radiation ( 63 ) or cisplatin ( 68 ). The synergism
with platinum-based chemotherapy was
attributed to the observation that upon this
treatment, CDK6 phosphorylates and stabil-
izes the FOXO3 transcription factor, thereby
promoting tumor cell survival. Consequently,
inhibition of CDK6 increases platinum sen-
sitivity by enhancing tumor cell death ( 91 ).
In several instances, co-treatment with
CDK4/6 inhibitors prevented the develop-
ment of resistance to other compounds or
inhibited the proliferation of resistant tumor
cells. Co-treatment of melanoma patient-
derived xenografts (PDXs) with ribociclib
plus the RAF inhibitor encorafenib delayed
or prevented development of encorafenib re-
sistance ( 92 ). PDXs that acquired encorafenib
resistance remained sensitive to the combination
of encorafenib plus ribociclib ( 59 ). Treatment
of BRAFV600E-mutant melanoma xenografts
with palbociclib plus the BRAFV600Einhibitor
PLX4720 prevented development of resistance
( 89 ). BRAFV600E-mutant melanoma cell lines
that acquired resistance to the BRAFV600E
inhibitor vemurafenib remained sensitive
to palbociclib or abemaciclib, and xenografts
underwent senescence and tumor regression
upon CDK4/6 inhibition ( 72 , 93 ). Treatment of
ALK-mutant, ALK kinase inhibitorÐresistant
neuroblastoma xenografts with palbociclib
restored the sensitivity to these compounds
( 94 ). A combination of PI3K and CDK4/6 in-
hibitors overcame the intrinsic and acquired
resistance of breast cancers to PI3K inhibitors
and resulted in regression ofPIK3CA-mutant
xenografts ( 88 ).
Up-regulation of cyclin D1 expression was
shown to mediate acquired resistance of HER2+
tumors to anti-HER2 therapies in a mouse
breast cancer model ( 95 ). Treatment of mice
bearing trastuzumab-resistant tumors or PDXs
of resistant HER2+mammary carcinomas with
abemaciclib restored the sensitivity of tumors
to HER2 inhibitors and inhibited tumor cell
proliferation. Moreover, in the case of treatment-
naïve tumors, co-administration of abemaciclib
significantly delayed the development of resist-
ance to anti-HER2 therapies ( 95 ).
Several anticancer treatments, such as che-
motherapy, target dividing cells. Because
CDK4/6 inhibitors block tumor cell proliferation,
they might impede the effects of chemotherapy.
Indeed, several reports have documented that
co-administration of CDK4/6 inhibitors antag-
onized the antitumor effects of compounds that
act during S phase (doxorubicin, gemcitabine,methotrexate, mercaptopurine) or mitosis
(taxanes) ( 96 , 97 ). However, some authors re-
ported synergistic effects ( 98 , 99 ), although the
molecular underpinnings are unclear.
A recent report documented that adminis-
tration of CDK4/6 inhibitors prior to taxanes
inhibited tumor cell proliferation and impeded
the effect of taxanes ( 100 ). By contrast, admin-
istration of taxanes first (or other chemo-
therapeutic compounds that act on mitotic
cells or cells undergoing DNA synthesis), fol-
lowed by CDK4/6 inhibitors, had a strong
synergistic effect. The authors showed that
by repressing the E2F-dependent transcrip-
tional program, CDK4/6 inhibitors impaired
the expression of genes required for DNA-
damage repair via homologous recombina-
tion. Because treatment of cancer cells with
chemotherapy triggers DNA damage, the im-
pairment of DNA-damage repair induced cyto-
toxicity, thereby explaining the synergistic
effect ( 100 ).
Cells with impaired homologous recombi-
nation rely on poly-(ADP-ribose) polymerase
(PARP) for double-stranded DNA-damage
repair, which renders them sensitive to PARP
inhibition. Indeed, a strong synergistic effect
has been demonstrated between CDK4/6Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 5 of 19
Table 2. Combination treatments that demonstrated synergy with CDK4/6 inhibitors in preclinical studies.TNBC, triple-negative breast cancer; AR,
androgen receptor; ER+, estrogen receptor–positive; T-ALL, T cell acute lymphoblastic leukemia; HER2+, human epidermal growth factor receptor 2–positive;
PI3K, phosphoinositide 3-kinase; EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor 1 receptor, InsR, insulin receptor.CDK4/6 inhibitor Synergistic target Inhibitor Disease
Palbociclib............................................................................................................................................................................................................................................................................................................................................PI3K Taselisib, pictilisib PIK3CA mutant TNBC
............................................................................................................................................................................................................................................................................................................................................AR Enzalutamide Androgen receptor–positive TNBC
............................................................................................................................................................................................................................................................................................................................................EGFR Erlotinib TNBC, esophageal squamous cell carcinoma
............................................................................................................................................................................................................................................................................................................................................RAF PLX4720 BRAF-V600E mutant melanoma
............................................................................................................................................................................................................................................................................................................................................MEK Trametinib KRAS mutant colorectal cancer
............................................................................................................................................................................................................................................................................................................................................MEK PD0325901 (mirdametinib) KRAS or BRAFV600E mutant colorectal cancer
............................................................................................................................................................................................................................................................................................................................................MEK MEK162 (binimetinib) KRAS mutant colorectal cancer
............................................................................................................................................................................................................................................................................................................................................MEK AZD6244 (selumetinib) Pancreatic ductal adenocarcinoma
............................................................................................................................................................................................................................................................................................................................................PI3K/mTOR BEZ235 (dactolisib), AZD0855, GDC0980 (apitolisib) Pancreatic ductal adenocarcinoma
............................................................................................................................................................................................................................................................................................................................................IGF1R/InsR BMS-754807 Pancreatic ductal adenocarcinoma
............................................................................................................................................................................................................................................................................................................................................mTOR Temsirolimus Pancreatic ductal adenocarcinoma
............................................................................................................................................................................................................................................................................................................................................mTOR AZD2014 (vistusertib) ER+breast cancer
............................................................................................................................................................................................................................................................................................................................................mTOR MLN0128 (sapanisertib) Intrahepatic cholangiocarcinoma
............................................................................................................................................................................................................................................................................................................................................mTOR Everolimus Melanoma, glioblastoma
Ribociclib............................................................................................................................................................................................................................................................................................................................................PI3K GDC-0941 (pictilisib), BYL719 (alpelisib) PIK3CA mutant breast cancer
............................................................................................................................................................................................................................................................................................................................................PDK1 GSK2334470 ER+breast cancer
............................................................................................................................................................................................................................................................................................................................................EGFR Nazartinib EGFR-mutant lung cancer
............................................................................................................................................................................................................................................................................................................................................RAF Encorafenib BRAF-V600E mutant melanoma
............................................................................................................................................................................................................................................................................................................................................mTOR Everolimus T-ALL
............................................................................................................................................................................................................................................................................................................................................Inflammation Glucocorticoid dexamethasone T-ALL
............................................................................................................................................................................................................................................................................................................................................g-Secretase Compound E T-ALL
Abemaciclib............................................................................................................................................................................................................................................................................................................................................HER2 Trastuzumab HER2+breast cancer
............................................................................................................................................................................................................................................................................................................................................EGFR and HER2 Lapatinib HER2+breast cancer
RAF LY3009120, vemurafenib KRAS mutant lung or colorectal cancer, NRAS or
............................................................................................................................................................................................................................................................................................................................................BRAF-V600E mutant melanoma
............................................................................................................................................................................................................................................................................................................................................Temozolomide (alkylating agent) GlioblastomaRESEARCH | REVIEW