title: Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer.
abstract: We report here on experimental and theoretical efforts to determine how best to combine drugs that inhibit HER2 and AKT in HER2(+) breast cancers. We accomplished this by measuring cellular and molecular responses to lapatinib and the AKT inhibitors (AKTi) GSK690693 and GSK2141795 in a panel of 22 HER2(+) breast cancer cell lines carrying wild type or mutant PIK3CA. We observed that combinations of lapatinib plus AKTi were synergistic in HER2(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) cell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment with lapatinib, AKTi or lapatinib + AKTi to shed light on the underlying signaling dynamics. This revealed that p-S6RP levels were less well attenuated by lapatinib in HER2(+)/PIK3CA(mut) cells compared to HER2(+)/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2(+)/PIK3CA(wt) cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CA(mut) cells following lapatinib + AKTi treatment. Responses of HER2(+) SKBR3 cells transfected with lentiviruses carrying control or PIK3CA(mut )sequences were similar to those observed in HER2(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) cell lines. We used a nonlinear ordinary differential equation model to support the idea that PIK3CA mutations act as downstream activators of AKT that blunt lapatinib inhibition of downstream AKT signaling and that the effects of PIK3CA mutations can be countered by combining lapatinib with an AKTi. This combination does not confer substantial benefit beyond lapatinib in HER2+/PIK3CA(wt) cells.
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.affiliation: University of California San Francisco, Division of Heme/Onc, San Francisco, California, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Laura
authors.initials: M
authors.lastname: Heiser
authors.affiliation: Netherlands Cancer Institute, Division of Biochemistry, Amsterdam, The Netherlands; University of Warwick, Centre for Complexity Science, Coventry, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Oates
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Nora
authors.initials: N
authors.lastname: Bayani
authors.affiliation: University of California, Berkeley, Department of Electrical Engineering and Computer Sciences, Berkeley, California, United States of America.
authors.forename: Sleiman
authors.initials: S
authors.lastname: Itani
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Esch
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Wallace
authors.initials: W
authors.lastname: Thompson
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Kuo
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Cooper
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Billig
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Safiyyah
authors.initials: S
authors.lastname: Ziyad
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Hung
authors.affiliation: Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Jakkula
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America; Lawrence Berkeley National Laboratories, Life Sciences Division, Berkeley, California, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Feiler
authors.affiliation: MD Anderson Cancer Center, Department of Systems Biology, Houston, Texas, United States of America.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: MD Anderson Cancer Center, Department of Systems Biology, Houston, Texas, United States of America.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: University of California, Berkeley, Department of Electrical Engineering and Computer Sciences, Berkeley, California, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Tomlin
authors.affiliation: Netherlands Cancer Institute, Division of Biochemistry, Amsterdam, The Netherlands.
authors.forename: Sach
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D003959:Diamines / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D042361:Mammary Glands, Human; D009154:Mutation; D010069:Oxadiazoles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D003959:Diamines; D000077341:Lapatinib; D010069:Oxadiazoles; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D038601:Ribosomal Protein S6; C000595149:GSK2141795; C528328:GSK690693; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human