title: CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.
abstract: Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sadhna R
authors.initials: SR
authors.lastname: Vora
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nayoon
authors.initials: N
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Huynh
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Pollack
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Manway
authors.initials: M
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehar
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Z Alexander
authors.initials: ZA
authors.lastname: Cao
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Pinzon-Ortiz
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. Electronic address: alan.huang@novartis.com.
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, 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* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein; C484760:PIK3CA protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human