Study: Alterations in Signaling Pathways Contribute to CDK4/6i Resistance in ER-Positive/HER2-Negative Breast Cancer

By identifying molecular alterations contributing to CDK4/6i resistance, researchers hope to better understand which patients with breast cancer will respond best to the therapy.

Although cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are the standard of care for patients with metastatic or advanced hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, approximately a quarter of patients will not respond or demonstrate progression within 6 months of initiating the therapy. By understanding molecular alterations contributing to intrinsic and required resistance, more successful clinical implementation of these agents may be possible.

Researchers from the Ontario Institute for Cancer Research characterized a panel of 15 ER-positive/HER2-negative cell lines using a NanoString PAM50-like assay, as well as next-generation sequencing. The cell lines were screened with 3 CDK4/6 inhibitors: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

A range of sensitivities to CDK4/6 inhibitors was observed based on molecular alterations, varying from 75 to 200nM in sensitive cell lines to 800nM to >5000nM in resistant cell lines. Following treatment with 1mM of a CDK4/6 inhibitor, resistant cell lines had increased expression of genes involved in DNA repair, replication, and cell cycle checkpoints, according to the researchers. They also demonstrated downregulation of genes involved in the regulation of cellular response to growth factor stimulation.

Downregulated genes included several members of the dual-specificity phosphatase (DUSP) family, which are responsible for negative regulation of mitogen-activated protein kinase (MAPK) signaling. This finding suggests a possible target population for treatment with CDK4/6 inhibitors, according to the researchers.

To determine whether the same pathways contributing to intrinsic resistance are also driving acquired resistance, 2 in-vitro models of acquired resistance to CDKi were developed by treating MCF7 and T47D cell lines with increasing concentrations of palbociclib or abemaciclib. In the MCF7 CDKi-resistant cell lines, researchers observed loss of RB1 as well as copy number gains of EGFR, BRCA1, and SMO. They also found increased activity of EGFR and MAPK signaling pathways and increased expression of cyclin E1.

These results suggest that changes in cell cycle and MAPK signaling pathways contribute to both intrinsic and acquired resistance to CDK4/6 inhibitors. With further research and better understanding, these findings could contribute to more targeted and successful clinical implementation of CDK4/6i therapies in patients with ER-positive/HER2-negative breast cancer.

REFERENCE

Bathurst L, Liao L, Crozier C, Bayani J, et al. Predicting sensitivity to CDK4/6 inhibition in ER+/HER2- breast cancer cell lines. Accessed Dec 5, 2019. https://plan.core-apps.com/sabcs2019/abstract/c3d31d6ffb8feb46fe802df1c904f3e0