PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. EXPERIMENTAL DESIGN: Three-dimensional laminin-rich extracellular matrix cultures of humanbreast 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. RESULTS: 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. CONCLUSIONS: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 cancerpatients.
Authors: Howard M Stern; Humphrey Gardner; Tomasz Burzykowski; Wafaa Elatre; Carol O'Brien; Mark R Lackner; Gary A Pestano; Angela Santiago; Ivonne Villalobos; Wolfgang Eiermann; Tadeusz Pienkowski; Miguel Martin; Nicholas Robert; John Crown; Paolo Nuciforo; Valerie Bee; John Mackey; Dennis J Slamon; Michael F Press Journal: Clin Cancer Res Date: 2015-02-03 Impact factor: 12.531
Authors: L Venturutti; R I Cordo Russo; M A Rivas; M F Mercogliano; F Izzo; R H Oakley; M G Pereyra; M De Martino; C J Proietti; P Yankilevich; J C Roa; P Guzmán; E Cortese; D H Allemand; T H Huang; E H Charreau; J A Cidlowski; R Schillaci; P V Elizalde Journal: Oncogene Date: 2016-05-09 Impact factor: 9.867
Authors: Saskia M Brachmann; Irmgard Hofmann; Christian Schnell; Christine Fritsch; Susan Wee; Heidi Lane; Shaowen Wang; Carlos Garcia-Echeverria; Sauveur-Michel Maira Journal: Proc Natl Acad Sci U S A Date: 2009-12-10 Impact factor: 11.205