Abstract
Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer. Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer. Significant GDC-0941 activity (EC(50) <1 micromol/L) was observed for >70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941 as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1 cells and tumor xenografts more sensitive to docetaxel. GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941 to HER2-directed treatment could augment clinical benefit in breast cancer patients.
Highlights
Cell lines were classified according to their HER2, estrogen receptor and progesterone receptor status, histologic subtype, HER3 expression levels, 3D lamininrich extracellular matrix (lrECM) culture morphophology, and PIK3CA genotype (25 – 28)
The effect of the GDC0941, trastuzumab, and pertuzumab combination on acinar size and morphology was shown to be additive by Bliss analysis. These results provide substantial support for the current view that HER2-HER3 catalytic activity is important for driving tumor cell proliferation and suggests a unique mechanism of action for GDC-0941 combination with trastuzumab and pertuzumab compared with small molecule HER2 inhibitors, such as lapatinib
We show that phosphatidylinositol 3-kinase (PI3K) inhibition acts in concert with trastuzumab, pertuzumab (Figs. 2 and 5), and docetaxel (Supplementary Fig. S5) to decrease the growth and morphogenesis of HER2-amplified tumor cells
Summary
Cellular activity of GDC-0941 on breast cancer cell lines in three-dimensional culture. Administration of 200 nmol/L lapatinib resulted in significant inhibition of epidermal growth factor receptor, HER2, HER3, and Akt phosphorylation in normal 3D lrECM culture conditions (Fig. 4A) as well as in the presence of exogenous heregulin (Supplementary Fig. S4). At this concentration, lapatinib treatment did not affect cell proliferation in. HCC1954 cells are classified in the basal-like subtype of HER2amplified breast cancer Because this subtype has been associated with poor prognosis in the clinic [36] it is encouraging that GDC-0941 treatment as a single agent and in combination with trastuzumab and pertuzumab showed potent efficacy in 3D lrECM assays (Fig. 5C). 3D lrECM models may have better predictive value for determining preclinical efficacy and can be used to select tumor cell lines for further in vivo characterization
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