Activation of the Phosphatidylinositol 3-kinase (PI3K) pathway is common in Estrogen receptor (ER)-positive breast cancer (BC) and it has been associated with resistance to endocrine therapies (ET). The crosstalk between the Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K pathways represents a strong rationale for co-targeting both axes to inhibit tumor growth. Moreover, combined treatment with PI3K and CDK4/6 inhibitors has been shown to overcome CDK4/6 inhibitor resistance in BC cells. We investigated the triple combination of ER, CDK4/6, and PI3K pathway inhibitors in ex vivo BC models as a novel strategy to overcome endocrine and CDK4/6-resistance.
We generated 25 ex vivo three dimensional spheroid culture models (organoids) from ER-positive BC samples, obtained from patients at surgery. After 5 days of treatment, we investigated anti-proliferative effects by MTT assay in these models with single agents, dual and triple combinations of Fulvestrant (F), Palbociclib (P) and Taselisib (T) as models of ET, CDK 4/6 and PI3K pathway inhibitors, respectively. We are also performing NGS analysis of both organoids and surgical samples to investigate predictive genomic biomarkers.
Our results demonstrated that combination of F, P and T had a synergistic effect on the inhibition of spheroids proliferation in ≈30% of the examined samples compared to single drug treatments. Two subgroups of samples with different behavior were identified: one group showed no effect after single or triple treatment with only ≈15% reduction in cell viability (probably resistant) while the other group exhibited greater sensitivity to treatments (e.g. lobular histotype). Ongoing NGS analysis including a full panel of cancer-related genes, such as genes involved in CDK and PI3K pathways resistance. We will analyze concordance between surgical samples and ex vivo models in terms of genomic features and we will explore predictive role of genomic alterations.
The results showed an encouraging activity of the triple combination of ER, CDK4/6, and PI3K pathway inhibitors in ex vivo models of ER-positive BC. The different effect of the treatments could suggest a correlation between mutation setting and individual response.
Clinical trial identification
Legal entity responsible for the study
University of Campania.
All authors have declared no conflicts of interest.