title: PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling.
abstract: Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting PIK3CA(H1047R). Induction of PIK3CA(H1047R) expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CA(H1047R) expression. Strikingly, although these Her2(+) PIK3CA(H1047R)-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CA(H1047R), a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA-activating mutations.
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ohlson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Xu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Symonds
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Isabella
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: W J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: N U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: I E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Roberts
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human