Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines

• Published in: Annals of oncology Vol. 21; no. 2; pp. 255 - 262
• Main Authors: Kataoka, Y., Mukohara, T., Shimada, H., Saijo, N., Hirai, M., Minami, H.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2010; Oxford University Press
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Chromones - administration & dosage; Chromones - pharmacology; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - genetics; Enzyme Activation - genetics; Female; Gene Amplification - physiology; Gynecology. Andrology. Obstetrics; HER2; Humans; Mammary gland diseases; Medical sciences; Morpholines - administration & dosage; Morpholines - pharmacology; Mutation, Missense - physiology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation - drug effects; Phosphorylation - genetics; PIK3CA; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Ribosomal Protein S6 Kinases - metabolism; Trastuzumab; Tumors; trastuzumab; breast cancer; PIK3CA; HER2; Antineoplastic agent; Breast disease; Enzyme; Targeted therapy; Transferases; erbB2 Gene; Breast cancer; Monoclonal antibody; Malignant tumor; In vitro; Human Epidermal growth factor Receptor 2; 1-Phosphatidylinositol 3-kinase; Resistance; Mammary gland diseases; C-Onc gene; Established cell line; Genetics; Mutation; Tumor cell; Protooncogene; Trastuzumab; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdp304

The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 μg/ml trastuzumab: 58% versus 92%; P=0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1μm CL-387,785: 21% versus 77%; P=0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype. Conclusions:PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.