Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells.

Brent N Rexer,Siprachanh Chanthaphaychith,Kimberly Brown Dahlman,Carlos L Arteaga

doi:10.1186/bcr3601

Brent N Rexer, Siprachanh Chanthaphaychith + Show 2 more

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https://doi.org/10.1186/bcr3601

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Abstract

IntroductionDespite multiple advances in the treatment of HER2+ breast cancers, resistance develops even to combinations of HER2 targeting agents. Inhibition of PI3K pathway signaling is critical for the efficacy of HER2 inhibitors. Activating mutations in PIK3CA can overlap with HER2 amplification and have been shown to confer resistance to HER2 inhibitors in preclinical studies.MethodsLapatinib-resistant cells were profiled for mutations in the PI3K pathway with the SNaPshot assay. Hotspot PIK3CA mutations were retrovirally transduced into HER2-amplified cells. The impact of PIK3CA mutations on the effect of HER2 and PI3K inhibitors was assayed by immunoblot, proliferation and apoptosis assays. Uncoupling of PI3K signaling from HER2 was investigated by ELISA for phosphoproteins in the HER2-PI3K signaling cascade. The combination of HER2 inhibitors with PI3K inhibition was studied in HER2-amplified xenograft models with wild-type or mutant PIK3CA.ResultsHere we describe the acquisition of a hotspot PIK3CA mutation in cells selected for resistance to the HER2 tyrosine kinase inhibitor lapatinib. We also show that the gain of function conferred by these PIK3CA mutations partially uncouples PI3K signaling from the HER2 receptor upstream. Drug resistance conferred by this uncoupling was overcome by blockade of PI3K with the pan-p110 inhibitor BKM120. In mice bearing HER2-amplified wild-type PIK3CA xenografts, dual HER2 targeting with trastuzumab and lapatinib resulted in tumor regression. The addition of a PI3K inhibitor further improved tumor regression and decreased tumor relapse after discontinuation of treatment. In a PIK3CA-mutant HER2+ xenograft, PI3K inhibition with BKM120 in combination with lapatinib and trastuzumab was required to achieve tumor regression.ConclusionThese results suggest that the combination of PI3K inhibition with dual HER2 blockade is necessary to circumvent the resistance to HER2 inhibitors conferred by PIK3CA mutation and also provides benefit to HER2+ tumors with wild-type PIK3CA tumors.

Highlights

Despite multiple advances in the treatment of human epidermal growth factor receptor 2 (HER2)+ breast cancers, resistance develops even to combinations of HER2 targeting agents
Amplification of the HER2 oncogene occurs in approximately 25% of human breast cancers and predicts response to therapies targeting human epidermal growth factor receptor 2 (HER2), including trastuzumab, a monoclonal antibody directed against HER2, and lapatinib, a tyrosine kinase inhibitor (TKI) of HER2 and
Recent clinical studies have suggested that targeting HER2-phosphoinositide 3-kinase (PI3K) signaling with combinations of agents that inhibit HER2 by different mechanisms is more effective than a single HER2 inhibitor; combining trastuzumab and lapatinib was more effective than trastuzumab alone in both the metastatic and neoadjuvant settings [20,21]; and combining two HER2 antibodies, trastuzumab and pertuzumab, prolonged survival longer than trastuzumab alone [22]

Summary

Introduction

Despite multiple advances in the treatment of HER2+ breast cancers, resistance develops even to combinations of HER2 targeting agents. Amplification of the HER2 oncogene occurs in approximately 25% of human breast cancers and predicts response to therapies targeting human epidermal growth factor receptor 2 (HER2), including trastuzumab, a monoclonal antibody directed against HER2, and lapatinib, a tyrosine kinase inhibitor (TKI) of HER2 and Alteration of the PI3K-Akt pathway is frequent in human cancers, and among the most frequent alterations are mutations in phosphoinositide 3-kinase catalytic subunit α (PIK3CA), the gene encoding the p110α catalytic subunit of PI3K These mutations cluster in hotspot regions in the helical and kinase domains of p110α [10,11] and confer a gain of function [12]. We have previously shown that, once resistance to HER2 inhibitors is established, inhibition of PI3K added to continued HER2 inhibition can overcome resistance [25]

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