Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer

Susana Ros,Yaniv Lubling,Sabine C Linn,Leonora W De Boo,Mafalda Oliveira,Alan J Wright,Richard D Baird,Pedram Razavi,Maurizio Scaltriti,Kevin M Brindle,Dimitra Georgopoulou,Alistair Martin,Alejandra Bruna,Oscar M Rueda,Rapahel Pelossof,Elizabeth Mannion,David Y Lewis,Giulia Lerda,Carlos Caldas,Ankita Sati Batra ,Dominique‐Laurent Couturier ,Robin Hesketh ,Paula D’santos ,De‐En Hu

doi:10.1016/j.ccell.2020.08.016

Abstract

SummaryPIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.

Highlights

PIK3CA encodes the p110a subunit of the class 1 phosphoinositide 3-kinase (PI3K), involved in regulating cell metabolism, proliferation, size, migration, angiogenesis, and survival (Fruman et al, 2017)
We investigated the effects of GDC-0032 on expression of HK-II in the upper part of the glycolytic pathway, and lactate dehydrogenase (LDHA) in the lower part
HK-II expression was decreased after treatment in both cell lines, whereas the drugresistant HCI-001 patient-derived breast cancer cells (PDTCs) showed sustained LDHA protein expression and activity (Figures 1B and 1C)

Summary

Introduction

PIK3CA encodes the p110a subunit of the class 1 phosphoinositide 3-kinase (PI3K), involved in regulating cell metabolism, proliferation, size, migration, angiogenesis, and survival (Fruman et al, 2017). Inhibition of PI3K signaling can inhibit tumor glycolysis by inhibiting release of aldolase from the cytoskeleton (Hu et al, 2016), suppressing membrane localization of glucose transporter 1 (Makinoshima et al, 2015), and by lowering the levels of c-Myc (Kalkat et al, 2017) and hypoxia-inducible factor 1 (HIF-1a) (Zhong et al, 2000), which drive expression of most of the glycolytic enzymes, including the A isoform of lactate dehydrogenase (LDHA) and hexokinase 2 (HK-II) (Dang et al, 2009) The activities of these enzymes, and inhibition of PI3K, can be assessed using metabolic imaging; for example, PET measurements of the uptake, phosphorylation, and trapping of the glucose analog, 2-deoxy-2-[18F]fluorodeoxyglucose ([18F] FDG), catalyzed by HK-II, and 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized 13C label exchange between [1-13C]pyruvate and the endogenous tumor lactate pool, catalyzed by LDHA (Brindle, 2008). The activities of these enzymes, and inhibition of PI3K, can be assessed using metabolic imaging; for example, PET measurements of the uptake, phosphorylation, and trapping of the glucose analog, 2-deoxy-2-[18F]fluorodeoxyglucose ([18F] FDG), catalyzed by HK-II, and 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized 13C label exchange between [1-13C]pyruvate and the endogenous tumor lactate pool, catalyzed by LDHA (Brindle, 2008). [18F]FDG-PET

Results

Discussion

Conclusion