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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Friday, January 6, 2023
According to Cristina Guarducci, PhD, of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, and colleagues, most patients with estrogen receptor (ER)-positive metastatic breast cancer develop resistance to CDK4/6 inhibitors. The results of their recent study, presented during the 2022 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting (Abstract GS3-07), suggest that the development of resistance to these agents may be the result of selection of preexisting resistant clones.
“We also demonstrate that the expression of the Y537S ER mutation impacts the clonal evolution and the mechanisms of acquired resistance to palbociclib but not to abemaciclib,” mentioned the investigators. “These results support the addition of a third drug to CDK4/6 inhibitors and endocrine therapy, early in treatment, to delay the selection of preexisting resistant clones and prolong the response to treatment and highlight differences between [these agents].”
Doxycycline-inducible Y537S ER-mutant MCF7 cells were transduced to promote the expression of the Y537S ER mutation. Palbociclib-resistant and abemaciclib-resistant cell models were created by culturing barcoded cells with increasing concentrations of each agent.
In the presence of the Y537S mutation versus the wild-type version, the palbociclib-resistant clones seemed to react differently. In contrast, the clones enriched in the abemaciclib-resistant cells appeared similar between ER-mutant and wild-type cells. These findings suggest that mutations to estrogen receptors may lead to decreased diversity of enriched clones in palbociclib-resistant cells; clonal selection appeared to be driven by cellular populations with definitive mutational landscapes.
Furthermore, all resistant cell models demonstrated different transcriptional profiles. In fact, single-cell RNA sequencing showed varying degrees of “intrasample heterogeneity.” There was an observed downregulation of ER, retinoblastoma protein, and p27, with an upregulation of p21. Cyclin D1 also appeared to be upregulated in palbociclib-resistant ER-mutant cells, whereas cyclin E was upregulated in abemaciclib-resistant cells.
Disclosure: Dr. Guarducci reported no conflicts of interest. For full disclosures of the other study authors, visit sabcs.org.
2022 San Antonio Breast Cancer Symposium
