Understanding Different Mechanisms of Resistance to Abemaciclib, Palbociclib Presents New Therapeutic Strategies

Research presented at the 2019 San Antonio Breast Cancer Symposium has found that mechanisms underlying cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance exhibited differentially altered pathways, such as DNA damage/repair pathways. By understanding and exploiting these differences, the researchers hope to develop novel therapies to overcome CDK4/6i therapy resistance.

Although endocrine therapy combined with CDK4/6 inhibitors has been found to improve the treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, patients inevitably develop clinical resistance during long-term treatment. In some cases, the authors noted, patients fail to respond within the first 3 months of treatment, demonstrating an intrinsic resistance, according to the study.

Although all CDK4/6 inhibitors have the same nominal targets, abemaciclib can inhibit other kinases that are not inhibited by palbociclib or ribociclib, leading to inhibited cell growth in retinoblastima (Rb)-deficient cells in which the other 2 drugs are ineffective, according to the researchers.

In an effort to examine the mechanisms of resistance to the different CDK4/6i, 3 models were generated and cell cycle changes were evaluated using western blot analysis and flow cytometry.

The western blot analysis found a dose-dependent downregulation of estrogen receptor alpha (ERα), Rb, Rb protein (p-Rb), and CDK inhibitor 1B (p27), whereas levels of cyclin E and p-CDK2 increased in a stepwise fashion in palbociclib-resistant cells, which were partially cross-resistant to abemaciclib and sensitive to CDK9 inhibitors.

Interestingly, a key mediator of DNA repair, Rad51, was downregulated in a stepwise manner only in abemaciclib-resistant cells and not in palbociclib-resistant cells. Based on this finding, the researchers further evaluated whether a combination therapy targeting DNA repair pathways plus abemaciclib could make palbociclib-resistant models more responsive to targets other than CDK inhibitors. Using organoid generated from patient-derived xenograft (PDX) models, they examined the combination of abemaciclib and niraparib (Zejula) and found a significant reduction in viability, number, and density of the organoids. In vivo, using the same PDX models, the combination treatment reduced the tumor growth rate and increased overall survival.

The authors concluded that because of the differentially altered pathways found in the mechanisms behind acquired palbociclib and abemaciclib resistance, it may be possible to exploit these differences to overcome CDK4/6i resistance.

REFERENCE

Knudsen ES, Navarro-Yepes J, Chen X, et al. Differential mechanisms of acquired resistance to abemaciclib versus palbociclib reveal novel therapeutic strategies for CDK4/6 therapy-resistant breast cancers [Abstract PD2-05]. Presented at: San Antonio Breast Cancer Symposium 2019. December 11, 2019. San Antonio, TX.