Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models.

Zhanfang Guo,Shunqiang Li,Rebecca Aft,Hua Sun,Jingqin Luo,Cynthia X Ma,Matthew J Ellis,Dean P Edwards,Cynthia Zhang,Jeremy Hoog,Sherri R Davies,Shixia Huang,Feng Gao,Li Ding,Tina Primeau

doi:10.3390/cancers12123857

Abstract

Simple SummaryThe objective of this study is to identify potential proteomic biomarkers in triple negative breast cancer (TNBC) that associate with response to PI3K inhibitors which are in clinical trials. We tested a panel of TNBC patient-derived xenograft (PDX) models for their tumor growth response to a pan-PI3K inhibitor, BKM120. Proteomic analyses by reverse phase protein array (RPPA) of 182 markers were performed on baseline and post short-term treatment PDX samples, to correlate with tumor growth response. We identified several baseline and treatment induced proteomic biomarkers in association with resistance. These results provide important insights for the development of PI3K inhibitors in TNBC. PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

Highlights

Triple negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive clinical course and frequent resistance to chemotherapy [1]
Five models were derived from African American women
We demonstrated that PI3K inhibition induces varying degrees of tumor growth inhibition, with five models demonstrating over 80% TGI (Figure 2)

Summary

Introduction

Triple negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive clinical course and frequent resistance to chemotherapy [1]. We evaluated the efficacy and response biomarkers of therapeutic targeting PI3K in a panel of TNBC PDX models. The importance of the PI3K pathway in the tumorigenesis of TNBC is supported by the preclinical observation that PTEN inactivation leads to “basal-like” breast cancer in animal models [16,17]. The pan-PI3K inhibitor BKM120 that was chosen for this study has been shown to induce a partial response in a patient with TNBC in the initial phase I study [19] and targets all of the class I PI3-kinase isoforms (p110α/β/δ/γ) [20]. We hypothesized that a subset of TNBC is growth-dependent on PI3K signaling and proteomic analysis of PDX models at baseline, and following short-term treatment could identify candidate biomarkers predictive of growth response to BKM120

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Conclusion