Targeting PI3K/mTOR Overcomes Resistance to HER2-Targeted Therapy Independent of Feedback Activation of AKT

Abstract

Purpose: Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies.Experimental Design: The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor (NVP-BKM120), a p110a isoform-specific PI3K inhibitor (NVP-BYL719), an mTORC1-specific inhibitor (NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor (NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines.Results: Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor-positive and/or HER2 þ cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2 þ breast cancer models. The PI3K/ mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1-2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo.

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

“…Collectively, PTEN loss could be a clinically valuable biomarker of resistance to trastuzumab-based chemotherapy in GEA. It has been suggested that combination therapy with PI3K inhibitors might be helpful in overcoming PTEN-loss-mediated trastuzumab resistance in GEA [16] and in breast cancer [7,27,28]. These present and previous results suggest that patients with HER2-overexpressing GEA and PTEN loss might require alternative therapy to trastuzumab therapy, or combination therapy with PI3K inhibitors.…”

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

“…The potential clinical value of the dual PI3K/mTOR inhibitors has been demonstrated by their significant inhibition of cell growth, and the induction of apoptosis and/or autophagy in a variety of tumor cancer cells [150][151][152], and these inhibitors have shown powerful effects in xenograft models of breast cancer [153], pancreatic cancer [154], melanoma [155], multiple myeloma [156], glioma [157], RCC [158], and acute myeloid leukemia (AML) [159].…”

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

“…www.impactaging.com 5 ) and imaged at the midpoint of study (36 days after inoculation). (D) Table describes the different experimental groups in which mice were subdivided to test different FS-115 concentrations and different treatment schedules.…”

“…On day 0, 1x10 5 MDA-MB-231-luc cells were diluted in 100μl HBSS and loaded into a 27-gauge needle for intracardiac injection. The following day, animals were first injected with D-luciferin (i.p.…”