title: Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer.
abstract: Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied in later stages of clinical development in multiple indications. Experience with other targeted agents suggests that clinical responses may be short-lived because of acquired resistance to therapy. Here, we report preclinical modeling of acquired resistance in a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified a heretofore-unreported mechanism of resistance, specifically high-level amplification of the mutant allele of PIK3CA, which resulted in a marked upregulation of PI3K signaling, enabling resistant cells to regain proliferative capacity at clinically relevant concentrations of the PI3K inhibitor, GDC-0941. We show that knockdown of the amplified PIK3CA mutant allele in these cells by small interfering RNA restored pathway signaling and sensitivity to PI3K inhibition at levels comparable to parental cells. These novel preclinical findings suggest that, in addition to assessment of other previously reported mechanisms of resistance, evaluation of PI3K copy number variation should be integrated into the exploratory analysis of biopsies obtained at disease progression.
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Huw
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: O'Brien
authors.affiliation: OncoMDx Laboratories, Palo Alto, CA, USA.
authors.forename: A
authors.identifier: 0000000261571355
authors.initials: A
authors.lastname: Pandita
authors.affiliation: OncoMDx Laboratories, Palo Alto, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Spoerke
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Hampton
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Wilson
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Lackner