title: Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.
abstract: BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Beausoleil
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Jakubik
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Nishtala
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Hall
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Klarisa
authors.initials: K
authors.lastname: Rikova
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: jengelman@partners.org.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011744:Pyrimidinones / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D011744:Pyrimidinones; 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; C585539:Alpelisib