IMPAKT 2017: Luminal Androgen Receptor Subtype of Triple-Negative Breast Cancer Demonstrates Sensitivity to CDK4/6 Inhibition
Researchers have identified a subtype of triple-negative breast cancer that may be responsive to inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6), according to findings presented by Asghar et al at the 2017 IMPAKT Breast Cancer Conference, held in Brussels (Abstract 44P). This study also sheds light on the mechanisms of resistance to CDK4/6 inhibition seen in other subtypes of triple-negative breast cancer. The IMPAKT conference is a collaborative effort by the European Society for Medical Oncology, the Breast International Group, and a multidisciplinary alliance of other European breast cancer organizations.
Study Background
Inhibitors of CDK4/6, such as palbociclib (Ibrance) and ribociclib (Kisquali), are indicated in combination with an aromatase inhibitor for the treatment of hormone receptor–positive breast cancer. However, triple-negative breast cancer has demonstrated resistance to these agents, prompting investigators to use several preclinical models to identify subtypes of triple-negative breast cancer that may be sensitive to CDK4/6 inhibition and to define the mechanisms of resistance in the disease.
Uzma Asghar, MD, of Breast Cancer Now, Institute of Cancer Research, London, headed a research team that used in vitro assays on 18 triple-negative breast cancer cell lines to quantify sensitivity to palbociclib and ribociclib. These agents were evaluated for in vivo drug toxicity, efficacy, and pharmacodynamics in mouse MDAMB453 xenograft models. The investigators performed single-cell phenotypic analysis using a CDK2 live cell reporter to understand resistance mechanisms to palbociclib using time-lapse imaging technology. Additional experimental techniques used by the researchers included immunofluorescence, western blotting, and immunohistochemistry (IHC) to determine molecular determinants of sensitivity.
Major Findings
The in vitro assays demonstrated that the luminal androgen receptor subtype of triple-negative breast cancer was highly sensitive to CDK4/6 inhibition compared to basal-like subtypes, which were resistant to CDK4/6 inhibition (P < .001). This sensitivity to palbociclib at 50 mg/kg was confirmed in vivo using MDAMB453 xenografts, wherein 7 partial responses (in a total of 10 xenographs) were observed.
Furthermore, IHC analysis revealed a reduction in tumor phosphorylated retinoblastoma levels—a key factor in cell-cycle progression—as early as 4 hours after treatment.
The mechanism of resistance was studied by phenotypic single-cell analysis using 3 palbociclib-sensitive and 3 palbociclib-resistant triple-negative breast cancer cell lines, which revealed distinct cell-cycle dynamics. Cells sensitive to palbociclib exited mitosis in a CDK2-low quiescent state that required CDK4/6 activity for cell-cycle reentry. However, cells resistant to palbociclib exited mitosis directly into a CDK2-high proliferative state with rapid transition to S phase and shorter cell cycles. Higher cyclin E1 levels were observed during the early G1 phase in resistant CDK2-high cells than measured in palbociclib-sensitive CDK2-low cells. The investigators demonstrated that these CDK2-high resistant cells could become sensitive to palbociclib by silencing cyclin E1.
The study also demonstrated that CDK4/6 inhibitors used in concert with PI3-kinase inhibitors in PIK3CA-mutant triple-negative breast cancer cell lines acted synergistically, and could make other triple-negative breast cancer subtype cell lines sensitive to palbociclib.
Conclusions
Based on these preclinical findings, the authors concluded that the luminal androgen receptor subgroup of triple-negative breast cancer demonstrated high sensitivity to CDK4/6 inhibition. They noted that an ongoing clinical trial is currently assessing CDK4/6 inhibition in triple-negative breast cancer (phase Ib PIPA).
They further determined distinct differences between cell-cycle exit from mitosis between palbociclib-sensitive and -resistant triple-negative breast cancer cell lines, with resistant cells having higher levels of cyclin E1. Blocking cyclin E1 activity made resistant cells, sensitive to palbociclib, leading to the conclusion that dysregulation of cyclin E1 expression is a key determinant of sensitivity to CDK4/6 inhibition.
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