Study Finds CDK4/6 Inhibitor-resistant ER+ Breast Cancer Hypersensitive to TTK Inhibition

The theonine tyronise kinase (TTK) inhibitor CFI-402257 has been found to be a promising therapeutic strategy for breast cancer patients whose disease progresses after cyclin-dependent kinase (CDK) 4/6 inhibition. A clinical trial testing this strategy is currently being launched.

The current results of the strategy were presented at the San Antonio Breast Cancer Symposium in San Antonio, TX.

Inhibitors of CDK 4 and 6 (CDK4/6i), in combination with hormonal therapies, have become the standard of care for the treatment of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. However, despite demonstrating significant improvements in progression-free survival, acquired resistance to these inhibitors invariably develops.

Recent analyses of clinical samples have identified emergent genomic alterations which indicate acquired resistance to CDK4/6i and have begun to investigate their processes. Because of the vulnerabilities of CDK4/6i, the researchers believe that it is imperative to improve the survival of this group of patients.

Therefore, they examined CDK4/6i resistance in ER-positive breast cancer cell lines using 2 complementary approaches: spontaneous development of resistance upon continuous exposure to palbociclib for 6 to 9 months and genetic engineering of RB1 loss of function. In both cases, palbociclib resistance was confirmed by colony formation and cell proliferation assays.

To identify potential therapeutic strategies for CDK4/6i-resistant cells, researchers tested the in vitro activity of novel cell cycle inhibitors using a sulforhodamine B (SRB) cytotoxicity assay. CFI-402257, a selective TTK inhibitor now in phase 1 testing, induced significantly increased cytotoxicity in different CDK4/6i-resistant models compared with parental cell lines, including but not exclusively, those with RB1 loss.

CFI-402257 treatment caused defects in cell cycle progression and increased DNA damage and genomic instability in CDK4/6i-resistant cells, whereas these effects were mild in parental, CDK4/6i-sensitive cell lines. In some cases, these phenotypes were accompanied by an increase in apoptotic signaling.

Analysis of the molecular determinants of these effects are currently being evaluated. In xenografts derived from MCF7 cells, CFI-402257 treatment completely reduced the growth of RB1-KO tumors and had a much less pronounced effect on wild-type tumors.

The results demonstrated that the TTK inhibitor CFI-402257 is a promising therapeutic strategy for patients with breast cancer who progress after CDK4/6 inhibition, according to the study.

REFERENCE

CDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition. Presented at the San Antonio Breast Cancer Symposium. Accessed December 3, 2019.