title: Enhanced PI3K p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective PI3K inhibitor.
abstract: Although the HER2-targeting agents trastuzumab and lapatinib have improved the survival of patients with HER2-positive breast cancer, resistance to these targeted therapies is a major challenge. To investigate mechanisms of acquired lapatinib resistance, we generated acquired lapatinib resistance cell models by extended exposure of two HER2-positive breast cancer cell lines to lapatinib. Genomic and proteomic analyses revealed that lapatinib-resistant breast cancer cells gained additional phosphoinositide 3-kinase (PI3K) activation through activating mutation in PI3K p110α and/or increasing protein expression of existing mutant p110α. p110α protein upregulation in lapatinib-resistant cells occurred through gene amplification or posttranscriptional upregulation. Knockdown of p110α, but not p110β, the other PI3K catalytic subunit present in epithelial cells, inhibited proliferation of lapatinib-resistant cells, especially when combined with lapatinib. Lapatinib-resistant xenograft growth was inhibited persistently by combination treatment with the p110α-selective PI3K inhibitor BYL719 and lapatinib; the drug combination was also well tolerated in mice. Mechanistically, the combination of lapatinib plus BYL719 more effectively inhibited Akt phosphorylation and, surprisingly, Erk phosphorylation, than either drug alone in the resistance model. These findings indicate that lapatinib resistance can occur through p110α protein upregulation-mediated, and/or mutation-induced, PI3K activation. Moreover, a combinatorial targeted therapy, lapatinib plus BYL719, effectively overcame lapatinib resistance in vivo and could be further tested in clinical trials. Finally, our findings indicate that p110β may be dispensable for lapatinib resistance in some cases. This allows the usage of p110α-specific PI3K inhibitors and thus may spare patients the toxicities of pan-PI3K inhibition to allow maximal dosage and efficacy.
authors.affiliation: Corresponding Author: Dihua Yu, Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. dyu@mdanderson.org.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Brady
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Seok
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction / Q000235:genetics
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases