Abstract 135: Targeted therapy of hormone receptor-positive breast cancer harboring PIK3CA and AKT1 genetic aberrations
Authors: Shariati Maryam , Evans Kurt W. , Scott Stephen M. , Chen Huiqin , Meric-Bernstam Funda 
Published: July 2017

Introduction: Molecular alterations in the PI3K/Akt/mTOR pathway is implicated in the pathogenesis of ER positive breast cancer with high frequency and therefore is the major focus of drug development. Activating mutations of this signaling pathway occur in more than 70% of breast tumors. The genetic alterations affecting major components of PI3K/Akt/mTOR include genes encoding the PI3K catalytic subunits p110α (PIK3CA) and the PI3K effector AKT1. Despite the efficacy of the available small molecule inhibitors for targeting different components of PI3K pathway, the contribution of PIK3CA and AKT1 genetic alterations to targeted therapy is not well understood. We speculated that ER positive breast tumors with PIK3CA and AKT1 alterations are more sensitive to PI3K and Akt inhibitors due to differential downstream pathway effectors.

Methods: We used a panel of isogenic MCF7 cell lines with oncogenic mutations of PIK3CA and AKT1 established through somatic cell gene targeting. A series of pharmacological compounds currently approved for breast cancer therapy or in clinical trials in targeting PI3K/Akt/mTOR pathway were evaluated using viability, clonogenic and cell cycle analysis assays. We performed functional proteomic profiling using reverse phase proteomic analysis (RPPA) to investigate differential protein expression in response to PI3K pathway inhibition in PIK3CA and AKT1 mutants MCF7 cell lines. In vivo experiment was done to evaluate the efficacy of the inhibitors in suppressing tumor growth.

Results: We demonstrated that PIK3CA (E545K) and AKT1 (E17K) sensitized cells to the inhibitory effects of BYL719 (p110α catalytic subunit inhibitor) and AZD5363 (pan-AKT kinase inhibitor) on survival, cell cycle progression and colony formation ability. The presence of PIK3CA and AKT1 mutations conferred growth advantage and exhibited increased proliferation in vitro and in vivo. These alterations dramatically increased Akt phosphorylation and induced activation of PI3K downstream effectors. RPPA analysis revealed several proteins differentially expressed in PIK3CA and AKT1 mutant cells compared with wild type (p-value &lt; 0.05).

Conclusion: PIK3CA and AKT1 mutations showed distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model. The presence of these genetic alterations in estrogen receptor (ER) positive breast cancer provided proliferative advantage and enhanced their sensitivity to targeted PI3K inhibition. These results will contribute to identify single agent and combination therapies targeting PI3K pathway with maximal activity at tolerated dose and selection for individuals most likely to be responsive based on their genomic alterations.

Citation Format: Maryam Shariati, Kurt W. Evans, Stephen M. Scott, Huiqin Chen, Funda Meric-Bernstam. Targeted therapy of hormone receptor-positive breast cancer harboring PIK3CA and AKT1 genetic aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 135. doi:10.1158/1538-7445.AM2017-135