title: Addition of the p110α inhibitor BYL719 overcomes targeted therapy resistance in cells from Her2-positive-PTEN-loss breast cancer.
abstract: Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine. In this study, we established an HER2-positive and PTEN loss cell line and confirmed it by western blot analysis. This cell line and its orthotopic xenograft models were exposed to p110α-specific inhibitor BYL719, p110β-specific inhibitor AZD6482, or pan-PI3K inhibitor BKM120, respectively, and the results showed sensitivity to both BYL719 and BKM120 but not AZD6482, which indicated a p110α-reliance for HER2-positive-PTEN-loss breast cancer. Then, the addition of BYL719 to HER2 antibody greatly reduced tumor growth both in vitro and in vivo, accompanied by inhibited PI3K effector phosphorylation. Therefore, our findings suggest that the combination of p110α-selective inhibitor BYL719 with HER2 antibody could be a potential strategy for more personalized treatment of HER2-posistive-PTEN-loss breast cancer; and in addition, the optimal schedule of this combination therapy needs to be further explored.
authors.affiliation: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
authors.forename: Bingfei
authors.initials: B
authors.lastname: Xu
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China. liupianamazing@126.com.
authors.forename: Pian
authors.initials: P
authors.lastname: Liu
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D000906:Antibodies; D000077341:Lapatinib; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013844:Thiazoles; D062367:ortho-Aminobenzoates; C578518:2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid; C571178:NVP-BKM120; C585539:Alpelisib; C508053:ERBB2 protein, human; C494929:PTEN protein, human
keywords: Breast cancer; HER2; PTEN; p110α; p110β