Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer

• DOI: 10.1038/oncsis.2013.46
• Publication Date: 2013-12-23T14:13:02Z
• Authors: L-Y Huw; C O'Brien; A Pandita; S Mohan; J M Spoerke; S Lu; Y Wang; G M Hampton; T R Wilson; M R Lackner
• Keywords: Acquired resistance

Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied later stages of development multiple indications. Experience with other targeted agents suggests that responses may be short-lived because acquired resistance to therapy. Here, we report preclinical modeling a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified heretofore-unreported mechanism resistance, specifically high-level amplification allele PIK3CA, which resulted marked upregulation PI3K signaling, enabling resistant cells regain proliferative capacity at clinically relevant concentrations inhibitor, GDC-0941. show knockdown amplified these by small interfering RNA restored pathway sensitivity inhibition levels comparable parental cells. These novel findings suggest that, addition assessment previously reported mechanisms evaluation copy number variation should integrated into exploratory analysis biopsies obtained disease progression.