PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers

Abstract

HER2 amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2-activation and Pten-loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.

Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase‐3β/β‐catenin pathway

“…At the translation level, PI3K is one of the primary upstream molecules of AKT, which is a heterodimeric enzyme consisted of p110 catalytic and p85 regulatory subunits. Several reports have shown that these two subunits modify PI3K activity to further regulate its target molecule AKT, supporting our hypothesis that solasodine probably targets p110α/β/δ or p85α/β to resist PI3K/AKT signal transduction. Protein kinase B is composed of three parts from the amino to the carboxyl terminal, including PH, kinase, and regulatory domains.…”

Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

“…Hyperactivation of the downstream PI3K-AKT pathway is the best characterized of these, and activating mutations in PIK3CA or loss of the lipid phosphatase PTEN each confer resistance to HER2-directed therapies in preclinical models (Berns et al, 2007; Nagata et al, 2004; Wang et al, 2015). Other proposed resistance mechanisms include alterations in the HER2 receptor, activation of parallel signaling pathways, overexpression of cyclin E, and variations in host-tumor immune interactions.…”

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

“…Mechanisms of lapatinib resistance have been widely studied in the literature. Common mechanisms include HER3 [3] and HER4 [4,27] amplification, ligand-mediated HER family hyperactivation [39,40] , PI3K hyperactivation [10,11,19] , and metabolic reprogramming of glucose [41,42] and glutamine [43] utilization pathways. Additionally, many of these also manifest as mechanisms of resistance to trastuzumab as well [44,45] .…”

“…Lipid metabolic rewiring is becoming increasingly recognized as a critical mechanism that promotes the growth and survival of cancer cells [12][13][14][15] and is often associated with maintenance of cancer cell stemness [16,17] and development of chemoresistance [17,18] . It is becoming clear that resistance mechanisms to kinase inhibitors in breast cancer often involve PI3K/ AKT/mTOR pathway hyperactivation [8][9][10][11]19] . Notably, PI3K/AKT/mTOR pathway plays a critical role in the regulation of several lipid metabolic processes such as FA synthesis [20] , FA uptake [21] , FA storage into lipid droplets [22,23] and FAO [24,25] .…”