BLU-222 is an investigational, potent, highly selective, orally bioavailable CDK2 inhibitor in clinical development. BLU-222 demonstrated robust antitumor activity in select CCNE1-high ovarian and endometrial cancer models. We used a combination of CRISPR whole genome screens coupled with targeted genetic and pharmacologic approaches in ovarian and endometrial cell lines to identify biological determinants to predict BLU-222 monotherapy activity. Rb and p16 expression were biomarkers that enriched for CDK2-dependency/BLU-222 sensitivity in CCNE1 overexpressed, non-amplified cells. Further, intact Rb and low p16 expression predicted a BLU-222 and CDK4/6 inhibitor combination response. BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination. These findings demonstrate that response to CDK2 inhibition by BLU-222 can be further predicted using a combinatorial biomarker signature that could refine patient selection criteria in CCNE1-high patients and support clinical development.

This content is only available via PDF.
Copyright held by the owner/author(s).
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
Attribution-NonCommercial-NoDerivatives

Article PDF first page preview

Article PDF first page preview

Supplementary data

Supplementary Information

Supplementary Figure legends and methods

- docx file
Supplementary Tables

Supplemental Tables

- xlsx file
Figure S1

Evaluation of CDK2-dependency in cell lines using CCLE/DepMap.

- jpeg file
Figure S2

CDK2-depletion induces antiproliferative effect in CCNE1-amplified cell lines.

- jpeg file
Figure S3

OVCAR-3 T2A and ES-2 BLU-222 PK and pRb PD from CDX studies.

- jpeg file
Figure S4

Cell cycle profiling in CCNE1-amplified and CCNE1-normal cell lines treated with BLU-222 for 24h.

- jpeg file
Figure S5

BLU-222 induced cell cycle phase changes in CCNE1 copy number normal, mRNA-high cell lines.

- jpeg file
Figure S6

Evaluating Rb and p16 as markers of response to BLU-222 in CCNE1-high cell lines

- jpeg file
Figure S7

Cyclin E1, Rb, and p16 protein expression measured by Western blot in ovarian and endometrial cell lines.

- jpeg file
Figure S8

BLU-22 antiproliferative effect is mediated by CDK2-RB-E2F axis.

- jpeg file
Figure S9

Evaluating ploidy and ubiquitin-related pathways in BLU-222 responders versus non-responders.

- jpeg file
Figure S10

Endometrial PDX model biomarker expression, PK/PD, and body weight measurements.

- jpeg file
Figure S11

Evaluating CDKN2A up- or downregulation in CCNE1-high ovarian and endometrial cell lines.

- jpeg file
Figure S12

Inhibition or knockdown of CDK4/6 sensitizes CCNE1-high, CDKN2A knockout cells to BLU-222.

- jpeg file
Figure S13

In vitro BLU-222 + ribociclib ZIP synergy plots

- jpeg file
Figure S14

BLU-222 + ribociclib PK and body weight measurements in OVK18, MFE-296, OVCAR-3 T2A xenograft studies.

- jpeg file
Figure S15

Additional BLU-222 and chemotherapy combination studies in mice in vivo.

- jpeg file
Figure S16

In vitro BLU-222 + carboplatin and BLU-222 + paclitaxel ZIP synergy plots.

- jpeg file