Science - USA (2022-01-14)

combination with CDK4/6 inhibitors blocked
proliferation of CDK4/6 inhibitor–resistant
cancer cells ( 111 , 141 , 158 – 161 ). Recently, two
CDK2-specific inhibitors, PF-07104091 ( 163 )
and BLU0298 ( 164 ), have been reported. PF-
07104091 is now being tested in a phase 2 cli-
nical trial in combination with palbociclib plus
antiestrogens. Another recent study identified a
novel compound, PF-3600, that inhibits CDK4/6
and CDK2 ( 165 ). PF3600 had potent antitumor
effects against xenograft models of intrinsic
and acquired resistance to CDK4/6 inhibition

( 165 ).Aphase2clinicaltrialiscurrentlyeval-

uating this compound as a single agent and in

combination with endocrine therapy in patients

with HR+/HER2–breast cancer and other can-

cer types.

Whole-exome sequencing of 59 HR+/HER2–

metastatic breast tumors from patients treated

with CDK4/6 inhibitors and anti-estrogens re-

vealed eight alterations that likely conferred re-

sistance:RB1loss; amplification ofCCNE2or

AURKA; activating mutations or amplification

ofAKT1,FGFR2, orERBB2; activating muta-

tions inRASgenes; and loss of ER expression.

The frequent activation of AURKA (in 27% of

resistant tumors) raises the possibility of com-

bining CDK4/6 inhibitors with inhibitors of

Aurora A kinase to overcome resistance ( 145 ).

In contrast to ER+mammary carcinomas,

TNBCs are overall resistant to CDK4/6 inhi-

bition ( 45 ). A subset of TNBCs display high num-

bers of lysosomes, which causes sequestration

of CDK4/6 inhibitors into the expanded lyso-

somal compartment, thereby preventing their

action on nuclear CDK4/6. Preclinical studies

Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 15 of 19

Additional target Inhibitor Immune

checkpoint

inhibitor

Tumor

type

Trial identifier

............................................................................................................................................................................................................................................................................................................................................

Proliferating cells +

PD-L1

Carboplatin + etoposide Atezolizumab SCLC: This trial investigates the

potential clinical benefit of trilaciclib

in preserving the bone marrow and

the immune system, and enhancing

antitumor efficacy when

administered with chemotherapy

NCT03041311

............................................................................................................................................................................................................................................................................................................................................

Proliferating cells Topotecan SCLC: This trial investigates the

potential clinical benefit of

trilaciclib in preserving the

bone marrow and the immune

system, and enhancing the

antitumor efficacy of

chemotherapy when

administered prior

to chemotherapy

NCT02514447

............................................................................................................................................................................................................................................................................................................................................

Proliferating cells Carboplatin + gemcitabine Metastatic TNBC: This study

investigates the potential

clinical benefit of trilaciclib in

preserving the bone marrow

and the immune system, and

enhancing the antitumor efficacy

of chemotherapy when administered

prior to chemotherapy

NCT02978716

............................................................................................................................................................................................................................................................................................................................................

Lerociclib

............................................................................................................................................................................................................................................................................................................................................

ER ER antagonist: fulvestrant HR+/HER2–metastatic

breast cancer

NCT02983071

............................................................................................................................................................................................................................................................................................................................................

EGFR............................................................................................................................................................................................................................................................................................................................................Osimertinib EGFR mutant NSCLC NCT03455829

SHR6390

............................................................................................................................................................................................................................................................................................................................................

ER ER antagonist: fulvestrant HR+/HER2–recurrent/

metastatic breast cancer

NCT03481998

............................................................................................................................................................................................................................................................................................................................................

Aromatase Letrozole, anastrozole HR+/HER2–recurrent/

metastatic breast cancer

NCT03966898, NCT03772353

............................................................................................................................................................................................................................................................................................................................................

EGFR/HER2 Pyrotinib HER2+gastric cancer, HER2+

metastatic breast cancer

NCT04095390, NCT03993964

............................................................................................................................................................................................................................................................................................................................................

AR............................................................................................................................................................................................................................................................................................................................................AR antagonists: SHR3680 metastatic TNBC NCT03805399

PF-06873600

............................................................................................................................................................................................................................................................................................................................................

Endocrine therapy Single agent and then

in combination with

endocrine therapy

HR+/HER2–metastatic breast

cancer, ovarian and fallopian tube

cancer, TNBC and other tumors

NCT03519178

............................................................................................................................................................................................................................................................................................................................................

FCN-473c

............................................................................................................................................................................................................................................................................................................................................

Aromatase Letrozole ER+/HER2–advanced

breast cancer

NCT04488107

............................................................................................................................................................................................................................................................................................................................................

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